The DOI matches its Crossref record; 255 of the 259 references it cites were found in a registry or an index; 37 of the 393 sources its claims cite were checked for support.
Lipid nanoparticles for mRNA delivery
Open accessAbstract
Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle-mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle-mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle-mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle-mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review summarizes lipid nanoparticle (LNP)–mRNA delivery, covering lipid design, physiological barriers, administration routes, manufacturing/storage/safety, and preclinical/clinical translation. It highlights the clinical milestone of COVID-19 LNP–mRNA vaccines and remaining challenges for broader mRNA therapeutics.
Key findings
- The COVID-19 vaccines mRNA-1273 and BNT162b2 use ionizable lipids SM-102 and ALC-0315, respectively, deliver nucleoside-modified mRNA encoding SARS-CoV-2 spike, and showed similar efficacy (~95%) in phase III trials.
- Clinical immunogenicity examples include mRNA-1440 (H10N8) at 100 μg inducing 78.3% HAI and 87.0% MN seroconversion, mRNA-1851 (H7N9) at 50 μg inducing 96.3% HAI and 100% MN seroconversion, and mRNA-1893 interim phase I at 10 and 30 µg inducing 94% and 100% seroconversion.
- Cancer vaccine data include FixVac, where after the eighth immunization more than 75% of patients generated immune responses against at least one tumour-associated antigen, and FixVac/anti-PD1 produced a >35% tumour regression rate in checkpoint inhibitor-experienced patients; mRNA-4157 monotherapy left 14/16 patients disease-free with median follow-up 8 months, while the combination cohort had 50% overall response rate and median progression-free survival 9.8 months.
- Protein-replacement examples include MRT5005 in cystic fibrosis, where three patients at the 16-mg dose had maximal PPFEV1 increases of 11.1%, 13.6% and 22.2% on day 8, and mRNA-1944, where single i.v. doses of 0.1, 0.3 and 0.6 mg kg−1 produced 2.0, 7.9 and 10.2 µg ml−1 CHKV-IgG at 24 h, with half-life about 69 days.
Methods
- Design: narrative Review; no primary experiments or new patient data are reported.
- Data/sample: synthesizes published literature and representative clinical trials listed in Tables 1 and 2 for infectious diseases, cancer and genetic disorders, plus preclinical studies.
- Analysis: qualitative synthesis of lipid chemistry, physiological barriers, administration routes, GMP/storage/safety considerations, and preclinical/clinical outcomes.
Limitations
- The paper states that the mechanism of endosomal escape has not yet been fully understood, the immunogenicity of cationic and ionizable lipids has not yet been fully understood, factors impacting long-term storage need investigation, and safety concerns remain.
- Evident from the text: as a narrative review, it does not use a systematic search or meta-analysis, and the clinical trial data presented are representative/interim rather than exhaustive; the literature is current to 2021.
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Claims the paper makes
132 Not checked yet · 13 Own interpretation · 6 Supported so far · 6 Partly supported · 6 No basis given · 5 Supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“mRNA has shown therapeutic potential in a range of applications, including viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing2,4,7–17.”
§ Lipid nanoparticles for mRNA delivery > Introduction
What the sources say
- Supportedcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
Figure 6 (Cancer immunotherapy section) lists infectious-disease vaccines, protein-replacement therapies, cancer immunotherapies, genetic reprogramming and genome engineering as potential mRNA applications; it includes influenza and RSV among the vaccine examples. The Preclinical and clinical applications section explains that these uses have been explored mainly in preclinical studies, consistent with the claim of therapeutic potential. (LLM, conf=0.93)
- Partly supportedcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). sourceExperimental — accuracy not yet measured
The Abstract describes mRNA as promising for vaccine development and protein replacement therapy, and the “mRNA cancer vaccines” section reports its use in cancer immunotherapy. The copy also discusses vaccines against viral infections, but the searched passages do not support the additional applications of cellular reprogramming or genome editing. (LLM, conf=0.87)
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [8] Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018). source
- Not checked yetcites [9] Guan, S. & Rosenecker, J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 24, 133–143 (2017). source
- Not checked yetcites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
- Partly supportedcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) describes RNA vaccines for infections and cancer immunotherapy and identifies mRNA as a means of supplying therapeutic proteins. The Messenger RNA and Genome editing sections (pages unavailable) support protein replacement and the use of Cas9 mRNA in genome editing. Our copy does not address cellular reprogramming or specifically identify viral vaccines, so it does not support the full list attributed to this source. (LLM, conf=0.86)
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Storage conditions of lipid nanoparticle–mRNA formulations are an important consideration for their clinical translation, because storage (aqueous, freezing and lyophilized storage) and the type of cryoprotectants (sucrose, trehalose or mannitol) affect the long-term stability of lipid nanoparticle–mRNA formulations168.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Stability and storage
What the sources say
- Supportedcites [168] Zhao, P. et al. Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact. Mater. 5, 358–363 (2020). source
The Introduction and Conclusion report that the authors tested aqueous, frozen, and lyophilized storage of lipid-like nanoparticle–mRNA formulations and found different stability outcomes. The Results and discussion section reports that sucrose, trehalose, and mannitol differed in their ability to preserve mRNA delivery efficiency. The paper identifies long-term storage as relevant to clinical translation. No page numbers are available in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“To improve the biocompatibility of lipid nanoparticles, biodegradable lipids can be applied76–78,108,179.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Supportedcites [76] Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013). source
The Introduction says that introducing biodegradability into the ionizable lipids used in LNPs may improve their biocompatibility. The Discussion reports substantial tolerability for a biodegradable lipid in rodents and nonhuman primates. Together, these passages support the cited sentence's description of biodegradable lipids as an approach to improving LNP biocompatibility, without establishing that every such lipid will do so. (LLM, conf=0.91)
- Not checked yetcites [77] Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018). source
- Supportedcites [78] Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019). source
The Discussion reports that including biodegradable lipids in LNPs improved tolerability and safety, including reduced injection-site inflammation after intramuscular delivery. This supports the citing sentence’s proposed use of biodegradable lipids to improve LNP biocompatibility. (LLM, conf=0.91)
- Not checked yetcites [108] Zhang, X. et al. Functionalized lipid-like nanoparticles for in vivo mRNA delivery and base editing. Sci. Adv. 6, eabc2315 (2020).
- Supportedcites [179] Zhang, X. et al. Biodegradable amino-ester nanomaterials for Cas9 mRNA delivery in vitro and in vivo. ACS Appl. Mater. Interfaces 9, 25481–25487 (2017). source
The Introduction states that nonbiodegradable lipidlike compounds may cause side effects and that biodegradable bonds substantially improved lipid tolerability in preclinical studies. This supports using biodegradable lipids to improve nanoparticle biocompatibility; the passage does not provide a page number. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation2,4,7,182.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Partly supportedcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). sourceExperimental — accuracy not yet measured
The passage on modified nucleosides (Box 1; page unavailable) says that incorporating pseudouridine into IVT mRNA can suppress its immune-stimulatory activity and help it avoid recognition by innate immune sensors. Our copy does not identify N1-methylpseudouridine as an example or establish the claimed effect for it (searched: N1-methylpseudouridine, m1ψ, methylpseudouridine). (LLM, conf=0.88)
- Supportedcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
The ‘Modulation of immunogenicity’ section says that exogenously delivered mRNA is sensed by innate immune receptors and that incorporating pseudouridine or 1-methylpseudouridine prevents activation of those sensors. It also reports more efficient translation of nucleoside-modified mRNA. (LLM, conf=0.94)
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [182] Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005). This study demonstrates that nucleoside modifications reduce the immunogenecity of in vitro-transcribed mRNA. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Cytotoxicity of lipid materials is also a safety concern, depending on the dose, lipid properties and cell types176,177.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [176] Lv, H., Zhang, S., Wang, B., Cui, S. & Yan, J. Toxicity of cationic lipids and cationic polymers in gene delivery. J. Control. Release 114, 100–109 (2006). source
- Supportedcites [177] Filion, M. C. & Phillips, N. C. Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells. Biochim. Biophys. Acta 1329, 345–356 (1997). source
The Discussion reports different toxicity thresholds for different cationic lipid formulations, supporting dependence on dose and lipid properties. It also finds toxicity in macrophages and U937 cells but not non-phagocytic T lymphocytes, and advises caution in using these liposomes for intracellular delivery to macrophages. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Apart from viral infections, lipid nanoparticle–mRNA vaccines have been reported to induce immune protection against parasitical31 and bacterial30,198 infections.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Partly supportedcites [31] Garcia, A. B. et al. Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection. Nat. Commun. 9, 2714 (2018). sourceExperimental — accuracy not yet measured
The Results section reports that PMIF RNA-replicon vaccination protected mice against Plasmodium re-infection, supporting the parasitic-infection part of the claim. The Methods section describes delivery with a cationic nanoemulsion, not a lipid nanoparticle formulation, so the specified vaccine formulation is not supported by this source. The bacterial-infection part has separate citations and is not attributed to this paper. (LLM, conf=0.88)
- Partly supportedcites [30] Maruggi, G. et al. Immunogenicity and protective efficacy induced by self-amplifying mRNA vaccines encoding bacterial antigens. Vaccine 35, 361–368 (2017). sourceExperimental — accuracy not yet measured
The Results (sections 2.2–2.3; page unavailable) report protection against bacterial infection in mouse models, supporting the bacterial-infection part of the claim. But section 2.2 says the vaccines tested were formulated with a cationic nanoemulsion (CNE), not lipid nanoparticles. The parasitic-infection part is attached to a different citation in the citing sentence and is not assessed here. (LLM, conf=0.88)
- Partly supportedcites [198] Arya, S., Lin, Q., Zhou, N., Gao, X. & Huang, J.-D. Strong immune responses induced by direct local injections of modified mRNA-lipid nanocomplexes. Mol. Ther. Nucleic Acids 19, 1098–1109 (2020). sourceExperimental — accuracy not yet measured
The Results section (“Immunogenicity and mRNA-Based AdsA Vaccination with Nanocomplex”; page unavailable) reports strong antigen-specific T-cell responses in mice given mRNA encoding an S. aureus antigen. It does not report a bacterial infection challenge or demonstrate protection against infection. The parasitic-infection part of the citing sentence is attached to a different citation. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Replacing the subgenomic sequence by a gene of interest enables high-level expression of desired proteins.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Supportedcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
Box 2, ‘Self-amplifying mRNA,’ says that viral structural genes are replaced by genes of interest under a subgenomic promoter, enabling high levels of protein production. This supports the claim’s description of replacing the sequence that encodes viral proteins, though the paper specifies that the subgenomic promoter is retained. (LLM, conf=0.88)
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Several personalized cancer vaccines using lipid nanoparticle–mRNA formulations have also entered clinical trials210–212.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [210] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-SITC2020.0798 (2020). source
- Not checked yetcites [211] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unreshectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source
- Supportedcites [212] Cafri, G. et al. mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest. 130, 5976–5988 (2020). source
The Patients and methods section reports that four patients with metastatic gastrointestinal cancer received a personalized neoantigen mRNA vaccine in a clinical trial. The vaccine-production passage describes formulation of that mRNA in lipid nanoparticles. This paper thus documents one example of the trials cited collectively, rather than needing to establish the total number on its own. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Similarly, the regulation of other tumour-associated genes, such as PLK1 (ref.133), Bax219, Maspin37, PUMA70 and PTEN220, can delay tumour growth in vivo.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Supportedcites [133] Rosenblum, D. et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci. Adv. 6, eabc9450 (2020). source
The citation to this paper is attached to PLK1, not to Bax, Maspin, PUMA or PTEN. In the Results sections on orthotopic GBM (Fig. 4) and metastatic ovarian cancer (Fig. 5), PLK1 editing inhibited tumour growth in mice. Page numbers were not provided in our copy. (LLM, conf=0.94)
- Not checked yetcites [219] Okumura, K. et al. Bax mRNA therapy using cationic liposomes for human malignant melanoma. J. Gene Med. 10, 910–917 (2008). source
- Supportedcites [37] Lara, H. et al. Targeting serous epithelial ovarian cancer with designer zinc finger transcription factors. J. Biol. Chem. 287, 29873–29886 (2012). source
This source is cited for Maspin, not the other genes, which have separate citations. The Discussion and Figure 5 report that nanoparticles delivering a Maspin-reactivating transcription factor significantly inhibited tumor growth in a mouse ovarian-cancer allograft model; page numbers are unavailable in our copy. (LLM, conf=0.93)
- Partly supportedcites [70] Jain, R. et al. MicroRNAs enable mRNA therapeutics to selectively program cancer cells to self-destruct. Nucleic Acid Ther. 28, 285–296 (2018). sourceExperimental — accuracy not yet measured
The citation attached to PUMA is supported in part: the Results and Fig. 5 report that PUMA mRNA induced tumour-cell damage and apoptosis in a mouse xenograft model. The reported measurements were taken six hours after injection; our copy does not show that PUMA treatment delayed tumour growth over time. (LLM, conf=0.85)
- Supportedcites [220] Islam, M. A. et al. Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat. Biomed. Eng. 2, 850–864 (2018). source
The citation to this paper is attached to PTEN, not to the other genes listed. The Discussion reports that nanoparticle delivery of PTEN mRNA restored PTEN function and inhibited primary and advanced tumour growth in vivo. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, mRNA can restore different types of protein, including secretory proteins, intracellular proteins and transmembrane proteins12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Supportedcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
The Messenger RNA (mRNA) section says mRNA can supplement cytoplasmic and large transmembrane proteins. Its Liver delivery of mRNA subsection also reports that delivery of factor IX mRNA produced factor IX in plasma, supporting the secreted-protein part of the paraphrase. Page numbers are unavailable in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Gene-editing components can be delivered by lipid nanoparticle–mRNA formulations to treat genetic diseases, including HTI92,238, hypercholesterolaemia81,96,105,239, lipoprotein metabolism disorders85 and transthyretin amyloidosis239,240, which has been demonstrated in preclinical studies.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Supportedcites [92] Yin, H. et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34, 328–333 (2016). source
The source supports the hereditary tyrosinaemia type I portion of the sentence, where this citation is attached. Its Abstract reports that lipid nanoparticles delivered Cas9 mRNA while an adeno-associated virus delivered the guide RNA and repair template, correcting a disease-causing mutation and rescuing symptoms in mice. The other listed diseases are attached to other citations and are not attributed to this source. (LLM, conf=0.92)
- Partly supportedcites [238] Song, C.-Q. et al. Adenine base editing in an adult mouse model of tyrosinaemia. Nat. Biomed. Eng. 4, 125–130 (2020). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [81] Liu, J. et al. Fast and efficient CRISPR/Cas9 genome editing in vivo enabled by bioreducible lipid and messenger RNA nanoparticles. Adv. Mater. 31, 1902575 (2019). sourceExperimental — accuracy not yet measured
The paper’s in vivo experiment reports that lipid nanoparticles delivered Cas9 mRNA and sgRNA targeting PCSK9, reducing serum PCSK9 in mice to 20% of control levels. It links PCSK9 to cholesterol homeostasis, supporting the hypercholesterolaemia-related portion of the citing sentence. It does not demonstrate treatment of hypercholesterolaemia or another genetic disease; the other named conditions have separate citations in the citing sentence. (LLM, conf=0.86)
- Supportedcites [96] Yin, H. et al. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. Nat. Biotechnol. 35, 1179–1187 (2017). source
The citation is attached to the hypercholesterolaemia portion of the sentence; the other conditions have separate citations. In Results (Evaluate e-sgRNA in vivo; page not provided), the paper reports delivering Cas9 mRNA and Pcsk9-targeting guide RNAs in lipid nanoparticles to mice, producing liver editing and a 35–40% fall in cholesterol. These are preclinical results, not a demonstration of treatment in people. (LLM, conf=0.91)
- Partly supportedcites [105] Jiang, C. et al. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 27, 440–443 (2017). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked yetcites [239] Conway, A. et al. Non-viral delivery of zinc finger nuclease mRNA enables highly efficient in vivo genome editing of multiple therapeutic gene targets. Mol. Ther. 27, 866–877 (2019). source
- Not checked yetcites [85] Qiu, M. et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc. Natl Acad. Sci. USA 118, e2020401118 (2021).
- Not checked yetcites [240] Finn, J. D. et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 22, 2227–2235 (2018). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics.”
§ Lipid nanoparticles for mRNA delivery > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“These lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution7,14,17.”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Other types of lipid
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of lipid nanoparticles7,11,14.”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Ionizable lipids
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Incorporating PEG-lipids further decreases recognition by the MPS and clearance by renal filtration17,127.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
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In the paper
“Following cellular internalization, lipid nanoparticles are usually trapped in endosomal compartments137–139.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [137] Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013). source
- Not checked yetcites [138] Gilleron, J. et al. Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013). source
- Not checked yetcites [139] Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015). source
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In the paper
“To function in vivo, lipid nanoparticle–mRNA formulations need to overcome multiple extracellular and intracellular barriers7,11 (Fig. 3a).”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
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In the paper
“Organ selectivity can also be achieved by adjusting the proportions of lipid components, for example, to design spleen-targeted mRNA vaccines26,27 or lung-targeted genome editing delivery systems114,134.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [26] Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016). source
- Not checked yetcites [27] Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021). source
- Not checked yetcites [114] Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). source
- Not checked yetcites [134] Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020). source
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In the paper
“Indeed, only a small amount of lipid nanoparticles may be able to escape from the endosome137–139.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [137] Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013). source
- Not checked yetcites [138] Gilleron, J. et al. Image-based analysis of lipid nanoparticle–mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013). source
- Not checked yetcites [139] Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015). source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Incorporation of biodegradable lipids improves the tolerability of lipid nanoparticles, by allowing fast metabolism while retaining mRNA delivery efficacy.”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Ionizable lipids
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In the paper
“In addition to cationic or ionizable lipids, lipid nanoparticle–mRNA formulations typically contain other lipid components, such as phospholipids (for example, phosphatidylcholine and phosphatidylethanolamine), cholesterol or polyethylene glycol (PEG)-functionalized lipids (PEG-lipids)7,14,17.”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Other types of lipid
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, endosomal escape is crucial for effective mRNA delivery.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [66] Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. 124, 8657–8661 (2012). source
- Not checked yetcites [76] Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013). source
- Not checked yetcites [77] Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018). source
- Not checked yetcites [78] Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019). source
- Not checked yetcites [88] Whitehead, K. A. et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat. Commun. 5, 4277 (2014). source
- Not checked yetcites [100] Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020). source
- Not checked yetcites [140] Alabi, C. A. et al. Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery. Proc. Natl Acad. Sci. USA 110, 12881–12886 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lipid components may activate host immune responses following systemic or local administration; for example, PEG-lipids could induce hypersensitivity reactions by stimulating the complement system127,169.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
- Not checked yetcites [169] Lila, A. S. A., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lipid nanoparticle–mRNA formulations may need different properties as vaccines than as therapeutics to achieve optimal therapeutic effects, for example, distinct biodistribution profiles.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Administration routes can greatly influence organ distribution, expression kinetics and therapeutic outcomes of lipid nanoparticle–mRNA formulations143,144.”
§ Lipid nanoparticles for mRNA delivery > Administration routes
What the sources say
- Not checked yetcites [143] Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217, 345–351 (2015). source
- Not checked yetcites [144] Melo, M. et al. Immunogenicity of RNA replicons encoding HIV Env immunogens designed for self-assembly into nanoparticles. Mol. Ther. 27, 2080–2090 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, the addition of 5% (w/v) sucrose or trehalose to lipid nanoparticle–mRNA formulations, stored in liquid nitrogen, allows maintenance of mRNA delivery efficacy for at least 3 months in vivo168.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Stability and storage
What the sources say
- Not checked yetcites [168] Zhao, P. et al. Long-term storage of lipid-like nanoparticles for mRNA delivery. Bioact. Mater. 5, 358–363 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, i.v. administration of mRNA vaccines has been shown to induce stronger antigen-specific cytotoxic T cell responses compared with local injection26,148,149.”
§ Lipid nanoparticles for mRNA delivery > Administration routes
What the sources say
- Not checked yetcites [26] Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016). source
- Not checked yetcites [148] Sayour, E. J. et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Oncoimmunology 6, e1256527 (2017). source
- Not checked yetcites [149] Broos, K. et al. Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon. Mol. Ther. Nucleic Acids 5, e326 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Lipid components may activate host immune responses following systemic or local administration; for example, PEG-lipids could induce hypersensitivity reactions by stimulating the complement system127,169.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
- Not checked yetcites [169] Lila, A. S. A., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, anti-PEG antibodies could result in fast systemic clearance of subsequently administered PEGylated nanoparticles by accelerated blood clearance127,169.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
- Not checked yetcites [169] Lila, A. S. A., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“These elements can be engineered to improve the stability and translational efficiency of mRNA2,4,7,13.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Good manufacturing practice
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Cationic and ionizable lipids have also been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species170–173.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [170] Kedmi, R., Ben-Arie, N. & Peer, D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 31, 6867–6875 (2010). source
- Not checked yetcites [171] Dokka, S., Toledo, D., Shi, X., Castranova, V. & Rojanasakul, Y. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes. Pharm. Res. 17, 521–525 (2000). source
- Not checked yetcites [172] Abrams, M. T. et al. Evaluation of efficacy, biodistribution, and inflammation for a potent siRNA nanoparticle: effect of dexamethasone co-treatment. Mol. Ther. 18, 171–180 (2010). source
- Not checked yetcites [173] Sedic, M. et al. Safety evaluation of lipid nanoparticle–formulated modified mRNA in the Sprague-Dawley rat and cynomolgus monkey. Vet. Pathol. 55, 341–354 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“After intravenous (i.v.) administration, many lipid nanoparticles can accumulate in the liver.”
§ Lipid nanoparticles for mRNA delivery > Administration routes
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, immune activation is undesirable for some mRNA applications, such as protein replacement therapies and genome editing.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The features of lipid nanoparticle–mRNA formulations have been thoroughly preclinically and clinically investigated, which has allowed the rapid development and clinical use of the COVID-19 lipid nanoparticle–mRNA vaccines.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [170] Kedmi, R., Ben-Arie, N. & Peer, D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 31, 6867–6875 (2010). source
- Not checked yetcites [173] Sedic, M. et al. Safety evaluation of lipid nanoparticle–formulated modified mRNA in the Sprague-Dawley rat and cynomolgus monkey. Vet. Pathol. 55, 341–354 (2018). source
- Not checked yetcites [174] Szebeni, J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol. Immunol. 61, 163–173 (2014). source
- Not checked yetcites [175] Lokugamage, M. P. et al. Mild innate immune activation overrides efficient nanoparticle-mediated RNA delivery. Adv. Mater. 32, 1904905 (2020). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, the clinical-grade COVID-19 vaccine, mRNA-1273, was produced within a month after the SARS-CoV-2 genome sequence was available15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Many other lipid nanoparticle–mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders2,4,8,12–14 (Tables 1,2).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [8] Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018). source
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In vivo application of lipid nanoparticles has been reported to induce liver and lung injuries in rodents170,173, which may be attributed to the cytotoxicity of the materials and the induction of”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [170] Kedmi, R., Ben-Arie, N. & Peer, D. The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation. Biomaterials 31, 6867–6875 (2010). source
- Not checked yetcites [173] Sedic, M. et al. Safety evaluation of lipid nanoparticle–formulated modified mRNA in the Sprague-Dawley rat and cynomolgus monkey. Vet. Pathol. 55, 341–354 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The first mRNA vaccine was made of liposomes and mRNA encoding an influenza virus nucleoprotein184.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [184] Martinon, F. et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 23, 1719–1722 (1993). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Since then, lipid nanoparticle–mRNA formulations have emerged as a potent alternative to conventional vaccine platforms, owing to their unique features4,15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These features make lipid nanoparticle–mRNA formulations a flexible and on-demand vaccine platform to rapidly respond to emerging infectious pathogens4,15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Finally, GMP-grade lipid nanoparticle-mRNA vaccines can be manufactured for specific antigens in a short period of time, compared with other vaccine platforms, such as recombinant proteins and inactivated vaccines2,4,15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This vaccine, designed in 1993, was able to induce virus-specific cytotoxic T cell responses in mice184.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [184] Martinon, F. et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 23, 1719–1722 (1993). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The vaccine mRNA-1893 is a clinical candidate that contains lipid nanoparticles with mRNA encoding Zika virus premembrane and envelope (prM-E) proteins193,194.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [193] Richner, J. M. et al. Vaccine mediated protection against Zika virus-induced congenital disease. Cell 170, 273–283.e12 (2017). source
- Not checked yetcites [194] Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e10 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Lipid nanoparticle–mRNA formulations are further being explored for Zika virus vaccines38,190,192–194.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [38] Erasmus, J. H. et al. A nanostructured lipid carrier for delivery of a replicating viral RNA provides single, low-dose protection against Zika. Mol. Ther. 26, 2507–2522 (2018). source
- Not checked yetcites [190] Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018). source
- Not checked yetcites [192] Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017). source
- Not checked yetcites [193] Richner, J. M. et al. Vaccine mediated protection against Zika virus-induced congenital disease. Cell 170, 273–283.e12 (2017). source
- Not checked yetcites [194] Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e10 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A 100-μg dose level induced 78.3% (HAI) and 87.0% (MN) seroconversion for H10N8 (refs156,157) and a 50-μg dose level resulted in 96.3% (HAI) and 100% (MN) seroconversion for H7N9 (refs156,157).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
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In the paper
“The mRNA-1440 and mRNA-1851 vaccines, which are composed of lipid nanoparticles and mRNA encoding haemagglutinin from H10N8 and H7N9 influenza viruses, respectively, have completed phase I clinical studies (NCT03076385 and NCT03345043)156,157.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“A 100-μg dose level induced 78.3% (HAI) and 87.0% (MN) seroconversion for H10N8 (refs156,157) and a 50-μg dose level resulted in 96.3% (HAI) and 100% (MN) seroconversion for H7N9 (refs156,157).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, the vaccines showed similar efficacy (~95%) in phase III clinical trials19–21.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [19] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source
- Not checked yetcites [20] Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020). source
- Not checked yetcites [21] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). References 19, 20, and 21 report safety and efficacy data about the SARS-CoV-2 lipid nanoparticle–mRNA vaccines BNT162b2 and mRNA-1273. source
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In the paper
“For example, a vitamin C-derived lipid nanoparticle allows mRNA delivery into primary macrophages136.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [136] Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020). source
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In the paper
“The coding region contains the sequences for an RNA-dependent RNA polymerase (RDRP), a promoter and structural viral proteins (also known as subgenomic sequence).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A series of clinical trials of mRNA vaccines have been initiated against human metapneumovirus, cytomegalovirus, respiratory syncytial virus, rabies virus and chikungunya virus (Table 1).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites Table 1
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“A single i.v. injection of 0.1, 0.3 and 0.6 mg kg−1 lipid nanoparticle–mRNA formulation produced 2.0, 7.9 and 10.2 µg ml−1 CHKV-IgG 24 h post injection, respectively.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites NCT03829384
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, the positive-strand mRNA serves as a genomic template for RDRP-mediated replication.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, lipid nanoparticle–mRNA vaccines have been tested against other viruses in animal models, including human immunodeficiency virus28,144,181,190, Powassan virus195, Venezuelan equine encephalitis virus196, dengue virus73 and Ebola virus197.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [28] Brito, L. A. et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol. Ther. 22, 2118–2129 (2014). source
- Not checked yetcites [144] Melo, M. et al. Immunogenicity of RNA replicons encoding HIV Env immunogens designed for self-assembly into nanoparticles. Mol. Ther. 27, 2080–2090 (2019). source
- Not checked yetcites [181] Pollard, C. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 21, 251–259 (2013). source
- Not checked yetcites [190] Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018). source
- Not checked yetcites [195] VanBlargan, L. A. et al. An mRNA vaccine protects mice against multiple tick-transmitted flavivirus infections. Cell Rep. 25, 3382–3392.e3 (2018). source
- Not checked yetcites [196] Samsa, M. M. et al. Self-amplifying RNA vaccines for Venezuelan equine encephalitis virus induce robust protective immunogenicity in mice. Mol. Ther. 27, 850–865 (2019). source
- Not checked yetcites [73] Zhang, M., Sun, J., Li, M. & Jin, X. Modified mRNA-LNP vaccines confer protection against experimental DENV-2 infection in mice. Mol. Ther. Methods Clin. Dev. 18, 702–712 (2020). source
- Not checked yetcites [197] Meyer, M. et al. Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease. J. Infect. Dis. 217, 451–455 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“After delivery into the cytoplasm, self-amplifying RNA (positive-strand mRNA) functions as a translation template for the production of the RDRP.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, the lipid nanoparticle–mRNA formulation mRNA-1944 (NCT03829384), designed to generate anti-chikungunya virus antibody (CHKV-IgG) in vivo, is under clinical evaluation.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites NCT03829384
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, circularization can improve the stability and half-life of mRNA in a physiological environment.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This self-amplification process allows the mass production of virions from limited amounts of virus at infection.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, FixVac, which was developed based on the RNA-LPX formulation, is a systemic mRNA vaccine encoding four non-mutated antigens of melanoma200.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [200] Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). This is a clinical trial on lipid nanoparticle–mRNA formulations for cancer immunotherapy. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Various cancer vaccines based on lipid nanoparticle–mRNA formulations are currently in clinical trials (Table 1).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites Table 1
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Meanwhile, the promoter in the negative-strand RNA is recognized by the RDRP, leading to the transcription of capped subgenomic RNA that encodes structural viral proteins.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, a combination of FixVac/anti-programmed cell death protein 1 (PD1) antibody augmented the antitumour effect of FixVac, resulting in a >35% tumour regression rate in immune checkpoint inhibitor-experienced patients200.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [200] Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). This is a clinical trial on lipid nanoparticle–mRNA formulations for cancer immunotherapy. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mRNA-2416 was generally well tolerated at different does levels214.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [214] Jimeno, A. et al. Abstract CT032: a phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. https://doi.org/10.1158/1538-7445.AM2020-CT032 (2020). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“mRNA vaccines can further be applied to overcome insufficient stimulation of chimeric antigen receptor (CAR) T cells in the therapy of solid tumours213.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [213] Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446–453 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, intranodal vaccination with free mRNA encoding ten neoepitopes of 13 patients with metastatic melanoma generated T cell immunity against multiple neoepitopes in all patients209.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [209] Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017). source
plaindirectn = 13- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, mRNA-4157 is a personalized cancer vaccine encoding up to 34 neoantigens210,211.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [210] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-SITC2020.0798 (2020). source
- Not checked yetcites [211] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unreshectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The interim analysis from the phase I trial (NCT02410733) showed that the metabolic activity of the spleen increased post the sixth immunization, indicating targeted delivery of FixVac and activation of resident immune cells200.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [200] Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). This is a clinical trial on lipid nanoparticle–mRNA formulations for cancer immunotherapy. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“In the monotherapy group, 14 out of 16 patients remained disease-free during the study, with a median follow-up time of 8 months210,211.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [210] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-SITC2020.0798 (2020). source
- Not checked yetcites [211] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unreshectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source
plainn = 16- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Alternatively to vaccination, a pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle–mRNA formulations delivering cytokines or co-stimulatory molecules33,106,161,163,214 (Table 2).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [33] Lei, S. et al. Efficient colorectal cancer gene therapy with IL-15 mRNA nanoformulation. Mol. Pharm. 17, 3378–3391 (2020). source
- Not checked yetcites [106] Li, Y. et al. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat. Cancer 1, 882–893 (2020). source
- Not checked yetcites [161] Li, Y. et al. In vitro evolution of enhanced RNA replicons for immunotherapy. Sci. Rep. 9, 6932 (2019). source
- Not checked yetcites [163] Hewitt, S. L. et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Sci. Transl Med. 11, eaat9143 (2019). source
- Not checked yetcites [214] Jimeno, A. et al. Abstract CT032: a phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. https://doi.org/10.1158/1538-7445.AM2020-CT032 (2020). source
plaindirectn = 22- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, mRNA-2416, a lipid nanoparticle encapsulating mRNA encoding human OX40L (a ligand of OX40), is in clinical evaluation for the treatment of patients with solid tumours (NCT03323398)214.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [214] Jimeno, A. et al. Abstract CT032: a phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. https://doi.org/10.1158/1538-7445.AM2020-CT032 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“To further improve vaccine efficacy, APC uptake and T cell activation can be optimized; for example, mannose-modified lipid nanoparticle–mRNA formulations are preferentially taken up by dendritic cells150,201,202.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [150] Van der Jeught, K. et al. Dendritic cell targeting mRNA lipopolyplexes combine strong antitumor T-cell immunity with improved inflammatory safety. ACS Nano 12, 9815–9829 (2018). source
- Not checked yetcites [201] Liu, L. et al. Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. Mol. Ther. 26, 45–55 (2018). source
- Not checked yetcites [202] Wang, Y., Zhang, L., Xu, Z., Miao, L. & Huang, L. mRNA vaccine with antigen-specific checkpoint blockade induces an enhanced immune response against established melanoma. Mol. Ther. 26, 420–434 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“Using a similar lipid nanoparticle formulation, mRNA vaccination has also been shown to elicit specific T cell responses in patients with gastrointestinal cancer (NCT03480152)212.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [212] Cafri, G. et al. mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest. 130, 5976–5988 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, the RNA-LPX formulation can be used to deliver mRNA encoding claudin 6 (CLDN6), a target for CAR T cell therapy in solid tumours213.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [213] Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446–453 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Therefore, the supplement of desired enzymes by lipid nanoparticle–mRNA formulations can slow down disease progression42,221.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [42] Prieve, M. G. et al. Targeted mRNA therapy for ornithine transcarbamylase deficiency. Mol. Ther. 26, 801–813 (2018). source
- Not checked yetcites [221] An, D. et al. Systemic messenger RNA therapy as a treatment for methylmalonic acidemia. Cell Rep. 21, 3548–3558 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Clinical trials of protein replacement therapies using lipid nanoparticle–mRNA formulations have mainly focused on inherited metabolic disorders thus far, including ornithine transcarbamylase deficiency (NCT03767270), methylmalonic acidaemia (NCT03810690) and propionic acidaemia (NCT04159103) (Table 2).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites Table 2
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Encouraged by these results, mRNA-2752, a lipid nanoparticle formulated with mRNA encoding human OX40L, IL-23 and IL-36γ, entered clinical evaluation (NCT03739931)163,215,216.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [163] Hewitt, S. L. et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Sci. Transl Med. 11, eaat9143 (2019). source
- Not checked yetcites [215] Bauer, T. et al. Abstract CT210: A Phase I, open-label, multicenter, dose escalation study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral injection alone and in combination with immune checkpoint blockade. Cancer Res. https://doi.org/10.1158/1538-7445.AM2019-CT210 (2019). source
- Not checked yetcites [216] Patel, M. R. et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. J. Clin. Oncol. 38, 3092–3092 (2020). source
plainn = 22- Asserted: passes — The authors put it forward as true.
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In the paper
“The therapeutic potential of mRNA-based protein replacement therapies has also been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225, Crigler–Najjar syndrome type 1 (ref.226), α1 antitrypsin deficiency227, methylmalonic acidaemia/aciduria228, arginase deficiency229, citrin defic”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [142] Cheng, Q. et al. Dendrimer-based lipid nanoparticles deliver therapeutic FAH mRNA to normalize liver function and extend survival in a mouse model of hepatorenal tyrosinemia type I. Adv. Mater. 30, 1805308 (2018). source
- Not checked yetcites [222] Jiang, L. et al. Systemic messenger RNA as an etiological treatment for acute intermittent porphyria. Nat. Med. 24, 1899–1909 (2018). source
- Not checked yetcites [223] Karadagi, A. et al. Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency. Sci. Rep. 10, 7052 (2020). source
- Not checked yetcites [224] Zhu, X. et al. Systemic mRNA therapy for the treatment of Fabry disease: preclinical studies in wild-type mice, Fabry mouse model, and wild-type non-human primates. Am. J. Hum. Genet. 104, 625–637 (2019). source
- Not checked yetcites [225] DeRosa, F. et al. Improved efficacy in a Fabry disease model using a systemic mRNA liver depot system as compared to enzyme replacement therapy. Mol. Ther. 27, 878–889 (2019). source
- Not checked yetcites [226] Apgar, J. F. et al. Quantitative systems pharmacology model of hUGT1A1-modRNA encoding for the UGT1A1 enzyme to treat Crigler-Najjar syndrome type 1. CPT Pharmacomet. Syst. Pharmacol. 7, 404–412 (2018). source
- Not checked yetcites [227] Connolly, B., Isaacs, C., Cheng, L., Asrani, K. H. & Subramanian, R. R. SERPINA1 mRNA as a treatment for alpha-1 antitrypsin deficiency. J. Nucleic Acids 2018, 8247935 (2018). source
- Not checked yetcites [228] An, D. et al. Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia. EBioMedicine 45, 519–528 (2019). source
- Not checked yetcites [229] Truong, B. et al. Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency. Proc. Natl Acad. Sci. USA 116, 21150–21159 (2019). source
- Not checked yetcites [230] Cao, J. et al. mRNA therapy improves metabolic and behavioral abnormalities in a murine model of citrin deficiency. Mol. Ther. 27, 1242–1251 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“These diseases are characterized by genetic deficiency of key enzymes, leading to an inability to process certain metabolic products12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mRNA-based protein replacement therapies have also emerged as a promising alternative to protein drugs, because mRNA can be translated into desired proteins with in situ post-translational modifications in host cells12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“To achieve effective translation, mRNA requires five structural elements, including the 5′ cap, 3′ poly(A) tail, protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Translate Bio has started a clinical trial (NCT03375047) to evaluate the safety and tolerability of nebulized lipid nanoparticle–mRNA formulations (MRT5005) in patients with cystic fibrosis.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites NCT03375047
plainn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“Lipid nanoparticles encapsulating CFTR mRNA can restore chloride secretion in Cftr-knockout mice68.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [68] Robinson, E. et al. Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Mol. Ther. 26, 2034–2046 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“According to the interim report, the three patients who received the 16-mg dose showed maximal PPFEV1 increases of 11.1%, 13.6% and 22.2%, respectively, on day 8 post nebulizing.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites NCT03375047
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The in vivo translation efficiency of mRNA molecules could be further increased by RNA engineering.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In addition, mRNA-based protein replacement therapies have been applied to haematological diseases (for example, haemophilia A232, haemophilia B91,104,233 and thrombotic thrombocytopaenic purpura234), central nervous system disorders67,152 (for example, Friedreich’s ataxia67), skin diseases235,236 (for example, elastin deficiency235) and hearing loss237 in preclinical”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [232] Chen, C.-Y. et al. Treatment of hemophilia A using factor VIII messenger RNA lipid nanoparticles. Mol. Ther. Nucleic Acids 20, 534–544 (2020). source
- Not checked yetcites [91] DeRosa, F. et al. Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system. Gene Ther. 23, 699–707 (2016). source
- Not checked yetcites [104] Li, B. et al. An orthogonal array optimization of lipid-like nanoparticles for mRNA delivery in vivo. Nano Lett. 15, 8099–8107 (2015). source
- Not checked yetcites [233] Ramaswamy, S. et al. Systemic delivery of factor IX messenger RNA for protein replacement therapy. Proc. Natl Acad. Sci. USA 114, E1941–E1950 (2017). source
- Not checked yetcites [234] Liu-Chen, S., Connolly, B., Cheng, L., Subramanian, R. R. & Han, Z. mRNA treatment produces sustained expression of enzymatically active human ADAMTS13 in mice. Sci. Rep. 8, 7859 (2018). source
- Not checked yetcites [67] Nabhan, J. F. et al. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia. Sci. Rep. 6, 20019 (2016). source
- Not checked yetcites [152] Anderson, D. M. et al. Stability of mRNA/cationic lipid lipoplexes in human and rat cerebrospinal fluid: methods and evidence for nonviral mRNA gene delivery to the central nervous system. Hum. Gene Ther. 14, 191–202 (2003). source
- Not checked yetcites [235] Lescan, M. et al. De novo synthesis of elastin by exogenous delivery of synthetic modified mRNA into skin and elastin-deficient cells. Mol. Ther. Nucleic Acids 11, 475–484 (2018). source
- Not checked yetcites [236] Blakney, A. K. et al. The skin you are in: design-of-experiments optimization of lipid nanoparticle self-amplifying RNA formulations in human skin explants. ACS Nano 13, 5920–5930 (2019). source
- Not checked yetcites [237] Miwa, T., Saito, H. & Akita, H. Lipid nanoparticles-encapsulated brain-derived neurotrophic factor mRNA delivered through the round window niche in the cochleae of guinea pigs. Exp. Brain Res. 239, 425–433 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Intellia Therapeutics further initiated a phase I clinical trial (NCT04601051) to study the safety, pharmacokinetics and pharmacodynamics of NTLA-2001 (lipid nanoparticles encapsulating gene-editing components) in patients with hereditary transthyretin amyloidosis.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites NCT04601051
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“In addition, circular RNA (circRNA) can be synthesized to optimize mRNA properties245,246 (Box 2).”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, barcoded nanoparticles allow in vivo high-throughput profiling of lipid nanoparticle distribution at the cell level121.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [121] Dahlman, J. E. et al. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc. Natl Acad. Sci. USA 114, 2060–2065 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, pH-responsive polymers, such as poly (β-amino ester), can be incorporated into lipid nanoparticles to facilitate endosomal escape of mRNA molecules160.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [160] Su, X., Fricke, J., Kavanagh, D. G. & Irvine, D. J. In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. Mol. Pharm. 8, 774–787 (2011). source
plainconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, optimization of the UTRs or the coding sequences results in increased protein expression, compared with wild-type controls107,244.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [107] Zeng, C. et al. Leveraging mRNA sequences and nanoparticles to deliver SARS-CoV-2 antigens in vivo. Adv. Mater. 32, 2004452 (2020). source
- Not checked yetcites [244] Thess, A. et al. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol. Ther. 23, 1456–1464 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Organ-specific and cell-specific delivery of lipid nanoparticles can be achieved by modulating the lipid structures.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Naturally derived membrane lipids (for example, exosomes and cell membranes) can also be applied for mRNA delivery116,249,250.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [116] Kim, J., Jozic, A. & Sahay, G. Naturally derived membrane lipids impact nanoparticle-based messenger RNA delivery. Cell. Mol. Bioeng. 13, 463–474 (2020). source
- Not checked yetcites [249] Yang, Z. et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 4, 69–83 (2020). source
- Not checked yetcites [250] Fang, R. H., Kroll, A. V., Gao, W. & Zhang, L. Cell membrane coating nanotechnology. Adv. Mater. 30, 1706759 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [64] Heyes, J., Palmer, L., Bremner, K. & MacLachlan, I. Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. J. Control. Release 107, 276–287 (2005). source
- Not checked yetcites [66] Jayaraman, M. et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew. Chem. 124, 8657–8661 (2012). source
- Not checked yetcites [76] Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013). source
- Not checked yetcites [77] Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018). source
- Not checked yetcites [78] Hassett, K. J. et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines. Mol. Ther. Nucleic Acids 15, 1–11 (2019). source
- Not checked yetcites [88] Whitehead, K. A. et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat. Commun. 5, 4277 (2014). source
- Not checked yetcites [97] Hajj, K. A. et al. Branched-tail lipid nanoparticles potently deliver mRNA in vivo due to enhanced ionization at endosomal pH. Small 15, 1805097 (2019). source
- Not checked yetcites [100] Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020). source
- Not checked yetcites [114] Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). source
- Not checked yetcites [140] Alabi, C. A. et al. Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery. Proc. Natl Acad. Sci. USA 110, 12881–12886 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, neurotransmitter-derived lipids can be used for mRNA delivery to the brain following i.v. injection82.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [82] Ma, F. et al. Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection. Sci. Adv. 6, eabb4429 (2020).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, alteration of the alkyl length of a lipid results in selective accumulation of lipid nanoparticle–mRNA formulations in the liver or spleen114.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [114] Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“For example, barcoding has been applied to study how the structure of cholesterol derivatives impact cell selectivity of lipid nanoparticles, revealing that selective accumulation in liver endothelial cells, Kupffer cells and hepatocytes125,126 depends on cholesterol structures.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [125] Paunovska, K. et al. Analyzing 2000 in vivo drug delivery data points reveals cholesterol structure impacts nanoparticle delivery. ACS Nano 12, 8341–8349 (2018). source
- Not checked yetcites [126] Paunovska, K. et al. Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses. Adv. Mater. 31, 1807748 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Such multifunctional lipid materials include self-adjuvant lipids, which boost vaccine efficacy117,119, and paclitaxel-derived lipids, which allow integration of chemotherapies and gene therapies for the treatment of cancer118.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [118] Zhang, C. et al. Chemotherapy drugs derived nanoparticles encapsulating mRNA encoding tumor suppressor proteins to treat triple-negative breast cancer. Nano Res. 12, 855–861 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition to serving as delivery component, lipids may have therapeutic effects synergistic with mRNA-encoded proteins.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Such multifunctional lipid materials include self-adjuvant lipids, which boost vaccine efficacy117,119, and paclitaxel-derived lipids, which allow integration of chemotherapies and gene therapies for the treatment of cancer118.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [117] Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019). source
- Not checked yetcites [119] Zhang, H. et al. Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling. Proc. Natl Acad. Sci. USA 118, e2005191118 (2021).
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 52
- Probably not a substantial claim. 20
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Chromatographic purification can remove double-stranded RNA, an analogue of viral genome, in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency2,4,7,183.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Supportedcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
The Box 1 passage says high-performance liquid chromatography eliminated dsRNA contaminants and the remaining immune stimulation in modified mRNA. The Protein-replacement therapies passage says improved purification protocols, used with nucleoside-modified IVT mRNA, increased translation. (LLM, conf=0.91)
- Supportedcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
The “Modulation of immunogenicity” section says chromatographic methods remove dsRNA contaminants from IVT mRNA, which otherwise trigger type I interferon production and inhibit translation. The “Optimization of mRNA translation and stability” section states that FPLC purification decreases immune activation and increases translation. (LLM, conf=0.94)
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Supportedcites [183] Kariko, K., Muramatsu, H., Ludwig, J. & Weissman, D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 39, e142 (2011). source
The Discussion states that HPLC purification removes dsRNA and other contaminants from in vitro-transcribed mRNA containing Ψ or m5C/Ψ, increases translation, and prevents the release of type I interferons and TNF-α. The claim is supported as a statement of what chromatographic purification can do; the reported elimination of immune activation applies to nucleoside-modified mRNA. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“First, mRNA is a non-infective and non-integrating agent with the ability to encode a broad range of antigens4,15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Supportedcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
The Abstract calls mRNA a “non-infectious, non-integrating platform.” The Basic mRNA vaccine pharmacology section says mRNA vaccines encode an antigen of interest, and the Self-amplifying mRNA vaccines section describes vaccines encoding antigens from diverse viruses and other pathogens. The provided passages do not specify page numbers. (LLM, conf=0.93)
- Supportedcites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source
The mRNA VACCINES section states that mRNA is non-infectious and non-integrating. It also describes encoding protein antigens from different pathogens, supporting the claim that mRNA can encode a broad range of antigens. (LLM, conf=0.94)
- Supportedcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
The “Advantages of mRNA vaccines” section says mRNA vaccines avoid infection concerns and do not pose a risk of genomic integration. The Introduction says mRNA can encode virtually any protein, supporting the claim that it can encode a broad range of antigens. No page numbers are available in our copy. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Second, mRNA vaccines can combine different antigen mRNAs; for example, six separate mRNAs have been incorporated in a cytomegalovirus vaccine, five of which encode a single pentameric antigen and one encodes a glycoprotein antigen185.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Supportedcites [185] John, S. et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine 36, 1689–1699 (2018). source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Circular RNA (circRNA) is a single-stranded RNA with a closed-loop structure.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Supportedcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
The Introduction describes circRNAs as lacking free ends, and Results (‘Long RNA circularization is assisted by homology’) describes the RNA transcript being excised as a covalently 5′-to-3′ linked circle. Together, these passages support the description of a single RNA strand with a closed-loop structure. (LLM, conf=0.89)
- Supportedcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
The Results section (page not provided) describes the RNA product as a covalently linked circle and reports tests confirming its circularity. The paper’s description of circRNAs as single-stranded RNAs with a contiguous structure supports the closed-loop description. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Every source the paper cites for this claim was checked and supports it.
In the paper
“The excessive accumulation of metabolites then results in clinical symptoms and may lead to death12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Supportedcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
The “Liver delivery of mRNA” section links excess methylmalonic acid in MMA to clinical symptoms and reports lifelong mortality. It also states that hyperammonemia in ornithine transcarbamylase deficiency can lead to neurological injury, coma, and death. The copy provides no page numbers for these passages. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The sequences of these elements regulate translation initiation, translation termination and post-transcriptional modification of mRNA molecules2,4.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Partly supportedcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). sourceExperimental — accuracy not yet measured
The 5′- and 3′-UTRs section says regulatory sequence elements modulate mRNA translation and stability, and the 5′ cap section links the cap to translation initiation. Figure 2 describes translation ending through mRNA degradation, but does not establish that the sequences of these elements regulate translation termination. The passages do not support the claim that those sequences regulate post-transcriptional modification of mRNA; Figure 2 instead describes post-translational modification of the protein product. Page numbers were not available in our copy. (LLM, conf=0.86)
- Partly supportedcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). sourceExperimental — accuracy not yet measured
The “Optimization of mRNA translation and stability” section says that UTR sequences affect translation and that the 5′ cap interacts with a translation initiation factor. It does not say that the sequences of these elements regulate translation termination or post-transcriptional modification of mRNA. Page numbers are not available in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release.”
§ Lipid nanoparticles for mRNA delivery > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This structural feature protects mRNA molecules from nuclease degradation and increases nanoparticle stability in physiological fluids17,46.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
- Not checked yetcites [46] Blakney, A. K., McKay, P. F., Yus, B. I., Aldon, Y. & Shattock, R. J. Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA. Gene Ther. 26, 363–372 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Ionizable lipids are protonated at low pH, which makes them positively charged, but they remain neutral at physiological pH (refs7,11,14).”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Ionizable lipids
What the sources say
- Not checked yetcites refs7,11,14
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, targeted delivery and endosomal escape remain challenging for mRNA delivery systems, highlighting the need for safe and effective mRNA delivery materials.”
§ Lipid nanoparticles for mRNA delivery > Introduction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lipid nanoparticle–mRNA formulations manufactured by rapid mixing exhibit a stable nanostructure17,130,131, in which mRNA molecules can be encapsulated in the interior core through electrostatic interactions with the lipids17,131.”
§ Lipid nanoparticles for mRNA delivery > Overcoming physiological barriers
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
- Not checked yetcites [130] Karnik, R. et al. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 8, 2906–2912 (2008). source
- Not checked yetcites [131] Leung, A. K., Tam, Y. Y. C., Chen, S., Hafez, I. M. & Cullis, P. R. Microfluidic mixing: a general method for encapsulating macromolecules in lipid nanoparticle systems. J. Phys. Chem. B 119, 8698–8706 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Trapped in endosomes, in which the pH is lower than in the extracellular environment, ionizable lipids are protonated and, therefore, become positively charged, which may promote membrane destabilization and facilitate endosomal escape of the nanoparticles7,11,14”
§ Lipid nanoparticles for mRNA delivery > Development of lipids for mRNA delivery > Ionizable lipids
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To translate lipid nanoparticle–mRNA systems from bench to bedside, good manufacturing practice (GMP) is crucial to ensure drug quality and therapeutic effects, in addition to considerations such as storage conditions and safety profiles.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Indeed, both i.m. and i.d. administration of lipid nanoparticle–mRNA vaccines produce robust immune responses at a well-tolerated dose in human trials156,157.”
§ Lipid nanoparticles for mRNA delivery > Administration routes
What the sources say
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“mRNA normally contains five structural elements, that is, a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4,7,13.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Good manufacturing practice
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This technique allows reproducible and scalable production of lipid nanoparticle–mRNA formulations that show high encapsulation efficiency and homogeneous size distribution17,131.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Good manufacturing practice
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
- Not checked yetcites [131] Leung, A. K., Tam, Y. Y. C., Chen, S., Hafez, I. M. & Cullis, P. R. Microfluidic mixing: a general method for encapsulating macromolecules in lipid nanoparticle systems. J. Phys. Chem. B 119, 8698–8706 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“mRNA-1273 is stored at −15 °C to −20 °C and is directly injected after thawing17, whereas BNT162b2 is stored at −60 °C to −80 °C and requires thawing and dilution by saline before injection17.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Stability and storage
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“To ameliorate safety concerns, numerous natural and synthetic polymers have been investigated as alternatives to PEG, of which several are under evaluation in clinical trials127,169.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
- Not checked yetcites [169] Lila, A. S. A., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The accelerated blood clearance phenomenon may change the bioavailability and biodistribution of the drug encapsulated in PEGylated nanoparticles and, thus, cause side effects127,169.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [127] Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010). source
- Not checked yetcites [169] Lila, A. S. A., Kiwada, H. & Ishida, T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J. Control. Release 172, 38–47 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“mRNA is susceptible to degradation and, thus, formulation buffers should be free of any ribonuclease contaminations2,4.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Good manufacturing practice
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“mRNA-1273 is stored at −15 °C to −20 °C and is directly injected after thawing17, whereas BNT162b2 is stored at −60 °C to −80 °C and requires thawing and dilution by saline before injection17.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Stability and storage
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Of note, the authorized COVID-19 mRNA vaccines are both stored in freezing conditions in the presence of sucrose17.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Stability and storage
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Finally, mRNA-1273 obtained Emergency Use Authorization from the FDA and conditional marketing authorization from the EMA within a year15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated, respectively15,17.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Nevertheless, immune responses to IVT mRNA may also suppress antigen expression and negatively affect vaccine efficacy175,180,181.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [175] Lokugamage, M. P. et al. Mild innate immune activation overrides efficient nanoparticle-mediated RNA delivery. Adv. Mater. 32, 1904905 (2020). source
- Not checked yetcites [180] Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008). source
- Not checked yetcites [181] Pollard, C. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 21, 251–259 (2013). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The IVT mRNA molecules used in the mRNA-1273 and BNT162b2 COVID-19 vaccines were prepared by replacing uridine with m1ψ17,19,21, and their sequences were optimized to encode a stabilized pre-fusion spike protein with two pivotal proline substitutions17,19,21.”
§ Lipid nanoparticles for mRNA delivery > Considerations for clinical translation > Safety profiles
What the sources say
- Not checked yetcites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source
- Not checked yetcites [19] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source
- Not checked yetcites [21] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). References 19, 20, and 21 report safety and efficacy data about the SARS-CoV-2 lipid nanoparticle–mRNA vaccines BNT162b2 and mRNA-1273. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“To address these concerns, the engineering of mRNA molecules (Box 1) and the design of lipid nanoparticles have been optimized2,4,7–17, which has contributed to the rapid development and clinical assessment15,17 of the two COVID-19 mRNA vaccines, mRNA-1273 (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [8] Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018). source
- Not checked yetcites [9] Guan, S. & Rosenecker, J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 24, 133–143 (2017). source
- Not checked yetcites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies2,4,8,12–14.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [8] Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018). source
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Both vaccines use ionizable lipid nanoparticles to deliver nucleoside-modified mRNA encoding the full-length spike protein of SARS-CoV-2 (Fig. 4).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [19] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source
- Not checked yetcites [20] Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020). source
- Not checked yetcites [21] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). References 19, 20, and 21 report safety and efficacy data about the SARS-CoV-2 lipid nanoparticle–mRNA vaccines BNT162b2 and mRNA-1273. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lipid nanoparticle–mRNA vaccines are also being investigated as influenza vaccines29,41,156,157,159,184,189–191, with some formulations in clinical trials (Table 1).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [29] Brazzoli, M. et al. Induction of broad-based immunity and protective efficacy by self-amplifying mRNA vaccines encoding influenza virus hemagglutinin. J. Virol. 90, 332–344 (2016). source
- Not checked yetcites [41] Perche, F. et al. Neutral lipopolyplexes for in vivo delivery of conventional and replicative RNA vaccine. Mol. Ther. Nucleic Acids 17, 767–775 (2019). source
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
- Not checked yetcites [159] Zhuang, X. et al. mRNA vaccines encoding the HA protein of influenza A H1N1 virus delivered by cationic lipid nanoparticles induce protective immune responses in mice. Vaccines 8, 123 (2020). source
- Not checked yetcites [184] Martinon, F. et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. Eur. J. Immunol. 23, 1719–1722 (1993). source
- Not checked yetcites [189] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source
- Not checked yetcites [190] Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018). source
- Not checked yetcites [191] Goswami, R. et al. Mannosylation of LNP results in improved potency for self-amplifying RNA (SAM) vaccines. ACS Infect. Dis. 5, 1546–1558 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Applying a prime–boost vaccination method, the vaccines induce high levels of antigen-specific antibodies and elicit robust T helper 1 cell responses19–21.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [19] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). source
- Not checked yetcites [20] Anderson, E. J. et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427–2438 (2020). source
- Not checked yetcites [21] Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020). References 19, 20, and 21 report safety and efficacy data about the SARS-CoV-2 lipid nanoparticle–mRNA vaccines BNT162b2 and mRNA-1273. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Other COVID-19 vaccines based on lipid nanoparticle–mRNA formulations are also under evaluation in different clinical phases (Table 1).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites Table 1
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Haemagglutinin is an essential surface antigen of influenza viruses156,157.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [156] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source
- Not checked yetcites [157] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). This paper reports a clinical trial on lipid nanoparticle–mRNA formulations as influenza vaccines. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, lipid nanoparticle–mRNA formulations have been applied to produce therapeutic proteins or antibodies39,75,145,146, to edit virus genomes105 and to engineer immune cells136.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [39] Erasmus, J. H. et al. Intramuscular delivery of replicon RNA encoding ZIKV-117 human monoclonal antibody protects against Zika virus infection. Mol. Ther. Methods Clin. Dev. 18, 402–414 (2020). source
- Not checked yetcites [75] Kim, J., Mukherjee, A., Nelson, D., Jozi c, A. & Sahay, G. Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2. Preprint at bioRxiv https://doi.org/10.1101/2020.07.24.205583 (2020). source
- Not checked yetcites [145] Pardi, N. et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat. Commun. 8, 14630 (2017). source
- Not checked yetcites [146] Thran, M. et al. mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol. Med. 9, 1434–1447 (2017). source
- Not checked yetcites [105] Jiang, C. et al. A non-viral CRISPR/Cas9 delivery system for therapeutically targeting HBV DNA and pcsk9 in vivo. Cell Res. 27, 440–443 (2017). source
- Not checked yetcites [136] Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“According to mRNA-1893 interim phase I data (NCT04064905) reported by Moderna, 10-µg and 30-µg dose levels (prime–boost regimen) induced 94% and 100% seroconversion, respectively, and both dose levels were generally well tolerated.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites NCT04064905
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Compared with regular mRNA, self-amplifying RNA (also termed replicon), which was originally derived from an alphavirus genome, has similar basic elements (5′ cap, 5′ and 3′ untranslated regions, 3′ poly(A) tail) and a long coding region.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The half-life of CHKV-IgG was about 69 days and the dose levels were reasonably well tolerated, including 0.3 mg kg−1 given twice a week apart.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites NCT03829384
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Adoptive transfer of macrophages engineered by delivering mRNA that encodes an antimicrobial peptide considerably reduced bacterial burden and increased survival in mice with multidrug-resistant bacterial sepsis136.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [136] Hou, X. et al. Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis. Nat. Nanotechnol. 15, 41–46 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The initial replication leads to negative-strand RNA, which acts as template for the generation of the positive-strand viral genome.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar to linear mRNA, the chemical modification of specific nucleotides and chromatographic purification can minimize immunogenicity of the RNA and increase translation.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“circRNA does not have a free 5′ cap or 3′ poly(A) tails and is, thus, unsusceptible to degradation by nucleases and more stable than linear RNA.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The attempt of mRNA-based cancer immunotherapies dates back to 1995, when i.m. injection of mRNA encoding carcinoembryonic antigens was shown to induce antigen-specific immune responses in mice199.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [199] Conry, R. M. et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 55, 1397–1400 (1995).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, circRNA without a stop codon reduces the frequency of ribosome detachment from the RNA, thereby enabling continuous translation and high protein expression.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The transient replication generates double-stranded RNA (dsRNA) and, thus, self-amplifying RNA tends to activate innate immune pathways.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics — developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Synthetic circRNA can be made by covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical methods.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Infectious diseases
What the sources say
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“After the eighth immunization, more than 75% of patients generated immune responses against at least one tumour-associated antigen, and CD8+ T cells played a major role in high-magnitude T cell responses200.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [200] Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). This is a clinical trial on lipid nanoparticle–mRNA formulations for cancer immunotherapy. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neoantigens, generated by somatic mutations in cancer cells, are usually tumour-specific and have high immunogenicity4,11.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Neoantigens are often different between individual patients, allowing the development of personalized vaccines4,11.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [4] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the combination group, the overall response rate in the cohort (human papillomavirus-negative, immune checkpoint inhibitor-naive, head and neck squamous cell carcinomas) was 50% and the median progression-free survival was 9.8 months210,211.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [210] Bauman, J. et al. 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-SITC2020.0798 (2020). source
- Not checked yetcites [211] Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unreshectable solid tumors. J. Clin. Oncol. 37, 2523 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“i.v. injection of this vaccine resulted in CLDN6 expression on splenic dendritic cells and macrophages213, promoting the activation of adoptively transferred CLDN6-CAR T cells and leading to suppression of large tumours in mice at a sub-therapeutic CAR T cell dose213.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [213] Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446–453 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Genetic disorders are caused by inherited or acquired gene mutations, which can cause abnormal protein expression12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the 22 patients (monotherapy: n = 15; combination: n = 7), six had stable disease, one had partial responses with 52% tumour reduction and five showed tumour shrinkage in treated and/or untreated sites215,216.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [215] Bauer, T. et al. Abstract CT210: A Phase I, open-label, multicenter, dose escalation study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral injection alone and in combination with immune checkpoint blockade. Cancer Res. https://doi.org/10.1158/1538-7445.AM2019-CT210 (2019). source
- Not checked yetcites [216] Patel, M. R. et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. J. Clin. Oncol. 38, 3092–3092 (2020). source
plainn = 22- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, restoration of the tumour suppressor gene TP53 can induce tumour cell apoptosis and sensitize tumour cells to chemotherapeutics in vivo118,218.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [118] Zhang, C. et al. Chemotherapy drugs derived nanoparticles encapsulating mRNA encoding tumor suppressor proteins to treat triple-negative breast cancer. Nano Res. 12, 855–861 (2019). source
- Not checked yetcites [218] Kong, N. et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci. Transl Med. 11, eaaw1565 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Moreover, the injected lesions showed an increase in OX40L expression and enhanced T cell activation214.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [214] Jimeno, A. et al. Abstract CT032: a phase 1/2, open-label, multicenter, dose escalation and efficacy study of mRNA-2416, a lipid nanoparticle encapsulated mRNA encoding human OX40L, for intratumoral injection alone or in combination with durvalumab for patients with advanced malignancies. Cancer Res. https://doi.org/10.1158/1538-7445.AM2020-CT032 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Lipid nanoparticle–mRNA formulations have also been investigated for ex vivo engineering of CAR T cells217 and for the production of antibodies, such as anti-CD20 (ref.146), anti-human epidermal growth factor receptor 2 (HER2)95 and anti-CD3/claudin 6 (ref.147).”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [217] Billingsley, M. M. et al. Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. Nano Lett. 20, 1578–1589 (2020). source
- Not checked yetcites [146] Thran, M. et al. mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol. Med. 9, 1434–1447 (2017). source
- Not checked yetcites [95] Rybakova, Y. et al. mRNA delivery for therapeutic anti-HER2 antibody expression in vivo. Mol. Ther. 27, 1415–1423 (2019). source
- Not checked yetcites [147] Stadler, C. R. et al. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nat. Med. 23, 815–817 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“mRNA-2752 was designed to induce a pro-inflammatory tumour microenvironment and to simultaneously strengthen T cell expansion, as well as memory responses215,216.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Cancer
What the sources say
- Not checked yetcites [215] Bauer, T. et al. Abstract CT210: A Phase I, open-label, multicenter, dose escalation study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral injection alone and in combination with immune checkpoint blockade. Cancer Res. https://doi.org/10.1158/1538-7445.AM2019-CT210 (2019). source
- Not checked yetcites [216] Patel, M. R. et al. A phase I study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral (iTu) injection alone and in combination with durvalumab. J. Clin. Oncol. 38, 3092–3092 (2020). source
plaindirectn = 22- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“mRNA-based protein replacement therapies are also being explored for heart241, liver242, lung243 and other organ diseases12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [241] Magadum, A., Kaur, K. & Zangi, L. mRNA-based protein replacement therapy for the heart. Mol. Ther. 27, 785–793 (2019). source
- Not checked yetcites [242] Trepotec, Z., Lichtenegger, E., Plank, C., Aneja, M. K. & Rudolph, C. Delivery of mRNA therapeutics for the treatment of hepatic diseases. Mol. Ther. 27, 794–802 (2019). source
- Not checked yetcites [243] Sahu, I., Haque, A. A., Weidensee, B., Weinmann, P. & Kormann, M. S. Recent developments in mRNA-based protein supplementation therapy to target lung diseases. Mol. Ther. 27, 803–823 (2019). source
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Progress in mRNA technologies and lipid nanoparticle-based delivery systems has allowed the development of mRNA COVID-19 vaccines at unprecedented speed, demonstrating the clinical potential of lipid nanoparticle–mRNA formulations and providing a powerful tool against the SARS-CoV-2 pandemic.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A variety of lipid nanoparticles have been explored and optimized for mRNA delivery, providing valuable information for the future design of mRNA therapeutics.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“MRT5005 was well tolerated at the 8-mg and 16-mg dose levels, and no serious side events were observed at any dose level.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites NCT03375047
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Patients with cystic fibrosis usually suffer from repeated airway infections and chronic respiratory problems because of the defective cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel on epithelial cells12.”
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
What the sources say
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“circRNA lacks the free ends necessary for nuclease-mediated degradation and, therefore, has a longer half-life than its linear mRNA counterpart245,246.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [245] Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018). source
- Not checked yetcites [246] Wesselhoeft, R. A. et al. RNA circularization diminishes immunogenicity and can extend translation duration in vivo. Mol. Cell 74, 508–520.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Polymers, such as polyethyleneimine, protamine and polyaspartamide derivatives, are already widely used for mRNA delivery7–17.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [7] Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017). source
- Not checked yetcites [8] Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018). source
- Not checked yetcites [9] Guan, S. & Rosenecker, J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 24, 133–143 (2017). source
- Not checked yetcites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).
- Not checked yetcites [11] Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019). source
- Not checked yetcites [12] Zhao, W., Hou, X., Vick, O. G. & Dong, Y. RNA delivery biomaterials for the treatment of genetic and rare diseases. Biomaterials 217, 119291 (2019). source
- Not checked yetcites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source
- Not checked yetcites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source
- Not checked yetcites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source
- Not checked yetcites [16] Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, charge-altering releasable transporters162,247 and modified dendrimers248 can effectively deliver mRNA molecules in vitro and in vivo.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
What the sources say
- Not checked yetcites [162] Haabeth, O. A. W. et al. Local delivery of Ox40l, Cd80, and Cd86 mRNA kindles global anticancer immunity. Cancer Res. 79, 1624–1634 (2019). source
- Not checked yetcites [247] McKinlay, C. J. et al. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. Proc. Natl Acad. Sci. USA 114, E448–E456 (2017). source
- Not checked yetcites [248] Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E4133–E4142 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biodegradable lipids enable fast elimination of lipid nanoparticles from plasma and tissues, improving their safety and tolerability.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Notably, biodegradable lipids are part of the mRNA-1273 and BNT162b2 COVID-19 mRNA vaccines.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, mRNA has shown great therapeutic potential in a number of clinical trials and in clinical applications.”
§ Lipid nanoparticles for mRNA delivery > Conclusions and future directions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper relies on this without support.
mRNA is unstable and has a short half-life.
“However, the instability and short half-life of mRNA need to be carefully considered.”
The paper relies on this without support.
Cancers are often accompanied by mutations in the genome.
“Cancers are often accompanied by mutations in the genome and, therefore, correction of these mutations could be an effective approach for cancer therapies.”
The paper relies on this without support.
Supplement of therapeutic proteins can relieve clinical symptoms but can often not provide lasting treatments or cures.
“The supplement of therapeutic proteins can relieve clinical symptoms but can often not provide lasting treatments or cures.”
The paper relies on this without support.
Testing and comparing the cell distribution of many different lipid nanoparticle formulations remains challenging.
“Testing and comparing the cell distribution of many different lipid nanoparticle formulations remains challenging.”
The paper relies on this without support.
Vaccines are the most effective approach to control and eradicate epidemics.
“Vaccines are the most effective approach to control and eradicate epidemics.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs (5–9).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While the ionizable lipid – in this case C3 – is a major determinant of intracellular delivery by both directly complexing with mRNA and facilitating endosomal escape, the remaining excipients also play critical roles: cholesterol provides stability and enables membrane fusion, DOPE supplies structural support, and PEG reduces aggregation and non-specific endocytosis (29).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [29]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In addition, LNPs have an ionizable lipid, which is predominantly neutral at physiological pH, as opposed to the quaternary lipid DOTMA, and this allows them to have an excellent combination of in vivo efficacy and low toxicity (8, 13).”
From Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection (2023) · cites this paper as [8]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“These findings may be related to the immunosuppressive TME of breast cancer [86, 87].”
From Nanosensitizer-assisted sonodynamic therapy for breast cancer (2025) · cites this paper as [87]
Experimental — accuracy not yet measuredIn the citing paper
“Previous studies have demonstrated that the use of BNT111 alone or in combination with PD-1 antibody can activate tumor antigen-specific CD4+ and CD8+ T cells and elicit durable immune responses.345,350–352”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [350]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Lipid nanoparticles for mRNA delivery > Preclinical studies and clinical trials > Genetic disorders
“including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225”
§ Lipid nanoparticles for mRNA delivery > References
“223. Karadagi A Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency Sci. Rep. 2020 10 7052 32341402 PMC7184591”
Citations
Cites
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2034577 · Cited by 14,592
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
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Self-citationmRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667
Diffusion of univalent ions across the lamellae of swollen phospholipids
Bangham, A. D., Standish, M. M., & Watkins, J. C. (1965) · Journal of Molecular Biology · doi:10.1016/s0022-2836(65)80093-6 · Cited by 4,664
Direct Gene Transfer into Mouse Muscle in Vivo
Wolff, J. A., Malone, R. W., Williams, P., Chong, W., Acsadi, G., Jani, A., & Felgner, P. L. (1990) · Science · doi:10.1126/science.1690918 · Cited by 4,173
Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives
Knop, K., Hoogenboom, R., Fischer, D., & Schubert, U. S. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.200902672 · Cited by 3,533
Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005) · Immunity · doi:10.1016/j.immuni.2005.06.008 · Cited by 2,728
Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.012 · Cited by 2,662
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
Sahin, U., Derhovanessian, E., Miller, M., Kloke, B.-P., Simon, P., Löwer, M., Bukur, V., Tadmor, A. D., Luxemburger, U., Schrörs, B., et al. (2017) · Nature · doi:10.1038/nature23003 · Cited by 2,488
mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474
Cited by
Sorted by citations
Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine
Overchuk, M., Weersink, R., Wilson, B. C., & Zheng, G. (2023) · ACS Nano · doi:10.1021/acsnano.3c00891 · Cited by 1,375
The role of lipid components in lipid nanoparticles for vaccines and gene therapy
Gregersen, C. H., Kulkarni, J. A., Witzigmann, D., Lind, M. L., Petersson, K., & Simonsen, J. B. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114416 · Cited by 1,271
Neoantigens: promising targets for cancer therapy
Xie, N., Shen, G., Gao, W., Huang, Z., Huang, C., & Fu, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01270-x · Cited by 1,020
Chemistry of Lipid Nanoparticles for RNA Delivery
Eygeris, Y., Gupta, M., Kim, J., & Sahay, G. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00544 · Cited by 917
Mendes, B. B., Conniot, J., Avital, A., Yao, D., Jiang, X., Zhou, X., Sharf-Pauker, N., Xiao, Y., Adir, O., Liang, H., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00104-y · Cited by 719
Metadata
- Authors
- Hou, X., Zaks, T., Langer, R., & Dong, Y.
- Affiliations
- The Ohio State University (US)
- Moderna Therapeutics (United States) (US)
- Corresponding author
- Zaks, Tal
- Dong, Yizhou
- Venue
- Nature Reviews Materials
- Published
- 2021-08-10
- Volume
- 6
- Issue
- 12
- Pages
- 1078-1094
- ISSN
- 2058-8437 (ISSN-L)
- PMC
- PMC8353930
- OpenAlex
- W3188940990
- Cited by
- 4,076
- References
- 259
- Citations by year
- 2026: 1075 · 2025: 1075 · 2024: 784 · 2023: 639 · 2022: 441 · 2021: 62
- FWCI
- 50.51
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-11-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Materials (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (4r37eb000244-34)
- National Institute of General Medical Sciences (R35GM119679)
- National Institute of Biomedical Imaging and Bioengineering (EB-000244, R01EB000244, R37-EB000244)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- lipid nanoparticles, mRNA delivery, mRNA vaccines, COVID-19 vaccines, clinical translation, good manufacturing practices, safety, route of administration, infectious diseases, cancer, genetic disorders, nucleic acid delivery
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