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Cited by 4,076RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryAdvancements in Transdermal Drug Delivery

Lipid nanoparticles for mRNA delivery

Open access
Hou, Xucheng, Zaks, Tal, Langer, Robert, Dong, Yizhou·2021·Nature Reviews Materials
DOI 10.1038/s41578-021-00358-0PMC PMC8353930
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Abstract

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.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41578-021-00358-0

Cites

255 of 255 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 393 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    mRNA has therapeutic potential in viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing.

    “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.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

  • Premisenone given

    Lipid nanoparticles have entered the clinic for mRNA delivery, including COVID-19 vaccines.

    “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.”
    Quote in the paperSubstantial claim
  • Premisecitation

    These other lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution.

    “These lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution7,14,17.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • Premisecitation

    The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo because neutral lipids have less interactions with anionic membranes of blood cells and improve biocompatibility.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

  • Premisecitation

    Incorporating PEG-lipids further decreases recognition by the MPS and clearance by renal filtration.

    “Incorporating PEG-lipids further decreases recognition by the MPS and clearance by renal filtration17,127.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

    • cites [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 in the free run.

  • Classified as probably not a substantial claim. 20
  • May combine two claims. 52

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    To function in vivo, mRNA requires safe, effective and stable delivery systems that protect it from degradation and allow cellular uptake and mRNA release.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This structural feature protects mRNA molecules from nuclease degradation and increases nanoparticle stability in physiological fluids.

    “This structural feature protects mRNA molecules from nuclease degradation and increases nanoparticle stability in physiological fluids17,46.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ionizable lipids are protonated at low pH, positively charged, but neutral at physiological pH.

    “Ionizable lipids are protonated at low pH, which makes them positively charged, but they remain neutral at physiological pH (refs7,11,14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites refs7,11,14

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Targeted delivery and endosomal escape remain challenging for mRNA delivery systems.

    “However, targeted delivery and endosomal escape remain challenging for mRNA delivery systems, highlighting the need for safe and effective mRNA delivery materials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lipid nanoparticle-mRNA formulations manufactured by rapid mixing exhibit a stable nanostructure, in which mRNA molecules can be encapsulated in the interior core through electrostatic interactions with the lipids.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

    • cites [130] Karnik, R. et al. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 8, 2906–2912 (2008). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trapped in endosomes, ionizable lipids are protonated and become positively charged, which may promote membrane destabilization and facilitate endosomal escape.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    To translate lipid nanoparticle-mRNA systems from bench to bedside, good manufacturing practice (GMP) is crucial to ensure drug quality and therapeutic effects.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both i.m. and i.d. administration of lipid nanoparticle-mRNA vaccines produce robust immune responses at a well-tolerated dose in human trials.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mRNA normally contains five structural elements: a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This technique allows reproducible and scalable production of lipid nanoparticle-mRNA formulations that show high encapsulation efficiency and homogeneous size distribution.

    “This technique allows reproducible and scalable production of lipid nanoparticle–mRNA formulations that show high encapsulation efficiency and homogeneous size distribution17,131.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA-1273 is stored at −15 °C to −20 °C and is directly injected after thawing.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Numerous natural and synthetic polymers have been investigated as alternatives to PEG, several of which are under evaluation in clinical trials.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The accelerated blood clearance phenomenon may change the bioavailability and biodistribution of the drug encapsulated in PEGylated nanoparticles and cause side effects.

    “The accelerated blood clearance phenomenon may change the bioavailability and biodistribution of the drug encapsulated in PEGylated nanoparticles and, thus, cause side effects127,169.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA is susceptible to degradation and, thus, formulation buffers should be free of any ribonuclease contaminations.

    “mRNA is susceptible to degradation and, thus, formulation buffers should be free of any ribonuclease contaminations2,4.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    BNT162b2 is stored at −60 °C to −80 °C and requires thawing and dilution by saline before injection.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The authorized COVID-19 mRNA vaccines are both stored in freezing conditions in the presence of sucrose.

    “Of note, the authorized COVID-19 mRNA vaccines are both stored in freezing conditions in the presence of sucrose17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA-1273 obtained Emergency Use Authorization from the FDA and conditional marketing authorization from the EMA within a year.

    “Finally, mRNA-1273 obtained Emergency Use Authorization from the FDA and conditional marketing authorization from the EMA within a year15,17.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source

      Not checked in the free run.

    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated for mRNA-1273, respectively.

    “About 2, 5 and 6 months from sequence availability, clinical trial phases I, II and III were initiated, respectively15,17.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source

      Not checked in the free run.

    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromatographic purification can remove double-stranded RNA in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune responses to IVT mRNA may suppress antigen expression and negatively affect vaccine efficacy.

    “Nevertheless, immune responses to IVT mRNA may also suppress antigen expression and negatively affect vaccine efficacy175,180,181.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [175] Lokugamage, M. P. et al. Mild innate immune activation overrides efficient nanoparticle-mediated RNA delivery. Adv. Mater. 32, 1904905 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    The IVT mRNA molecules used in the mRNA-1273 and BNT162b2 COVID-19 vaccines were prepared by replacing uridine with m1ψ, and their sequences were optimized to encode a stabilized pre-fusion spike protein with two pivotal proline substitutions.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Engineering of mRNA molecules and design of lipid nanoparticles have been optimized, contributing to the rapid development and clinical assessment of the two COVID-19 mRNA vaccines.

    “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.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies.

    “Moreover, mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies2,4,8,12–14.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both COVID-19 mRNA vaccines use ionizable lipid nanoparticles to deliver nucleoside-modified mRNA encoding the full-length spike protein of SARS-CoV-2.

    “Both vaccines use ionizable lipid nanoparticles to deliver nucleoside-modified mRNA encoding the full-length spike protein of SARS-CoV-2 (Fig. 4).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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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  • May combine two claims.

    Premisecitation

    mRNA is a non-infective and non-integrating agent with the ability to encode a broad range of antigens.

    “First, mRNA is a non-infective and non-integrating agent with the ability to encode a broad range of antigens4,15,17.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source

      Not checked in the free run.

    • cites [17] Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 antigen.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipid nanoparticle-mRNA vaccines are being investigated as influenza vaccines, with some formulations in clinical trials.

    “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).”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [189] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Applying a prime-boost vaccination method, the COVID-19 mRNA vaccines induce high levels of antigen-specific antibodies and elicit robust T helper 1 cell responses.

    “Applying a prime–boost vaccination method, the vaccines induce high levels of antigen-specific antibodies and elicit robust T helper 1 cell responses19–21.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other COVID-19 vaccines based on lipid nanoparticle-mRNA formulations are under evaluation in different clinical phases.

    “Other COVID-19 vaccines based on lipid nanoparticle–mRNA formulations are also under evaluation in different clinical phases (Table 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Haemagglutinin is an essential surface antigen of influenza viruses.

    “Haemagglutinin is an essential surface antigen of influenza viruses156,157.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Lipid nanoparticle-mRNA formulations have been applied to produce therapeutic proteins or antibodies, to edit virus genomes and to engineer immune cells.

    “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.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interim phase I data for mRNA-1893 showed that 10-μg and 30-μg dose levels (prime-boost regimen) induced 94% and 100% seroconversion, respectively, and both dose levels were generally well tolerated.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT04064905

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Self-amplifying RNA has similar basic elements to regular mRNA and a long coding region.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites NCT03829384

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 sepsis.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Initial replication of self-amplifying RNA leads to negative-strand RNA, which acts as a template for the generation of the positive-strand viral genome.

    “The initial replication leads to negative-strand RNA, which acts as template for the generation of the positive-strand viral genome.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chemical modification of specific nucleotides and chromatographic purification can minimize immunogenicity of RNA and increase translation.

    “Similar to linear mRNA, the chemical modification of specific nucleotides and chromatographic purification can minimize immunogenicity of the RNA and increase translation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Circular RNA 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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 mice.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Conry, R. M. et al. Characterization of a messenger RNA polynucleotide vaccine vector. Cancer Res. 55, 1397–1400 (1995).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Circular RNA is a single-stranded RNA with a closed-loop structure.

    “Circular RNA (circRNA) is a single-stranded RNA with a closed-loop structure.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circular RNA without a stop codon reduces the frequency of ribosome detachment from the RNA, thereby enabling continuous translation and high protein expression.

    “Moreover, circRNA without a stop codon reduces the frequency of ribosome detachment from the RNA, thereby enabling continuous translation and high protein expression.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Transient replication of self-amplifying RNA generates double-stranded RNA and thus self-amplifying RNA tends to activate innate immune pathways.

    “The transient replication generates double-stranded RNA (dsRNA) and, thus, self-amplifying RNA tends to activate innate immune pathways.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Synthetic circular RNA can be made by covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical methods.

    “Synthetic circRNA can be made by covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical methods.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After the eighth immunization with FixVac, 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 responses.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neoantigens, generated by somatic mutations in cancer cells, are usually tumour-specific and have high immunogenicity.

    “Neoantigens, generated by somatic mutations in cancer cells, are usually tumour-specific and have high immunogenicity4,11.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Neoantigens are often different between individual patients, allowing the development of personalized vaccines.

    “Neoantigens are often different between individual patients, allowing the development of personalized vaccines4,11.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    In the combination group of a phase I study of mRNA-4157, 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 months.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    i.v. injection of a CLDN6 mRNA vaccine resulted in CLDN6 expression on splenic dendritic cells and macrophages, 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 dose.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Genetic disorders are caused by inherited or acquired gene mutations, which can cause abnormal protein expression.

    “Genetic disorders are caused by inherited or acquired gene mutations, which can cause abnormal protein expression12.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    In 22 patients treated with mRNA-2752 (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 sites.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restoration of the tumour suppressor gene TP53 can induce tumour cell apoptosis and sensitize tumour cells to chemotherapeutics in vivo.

    “For example, restoration of the tumour suppressor gene TP53 can induce tumour cell apoptosis and sensitize tumour cells to chemotherapeutics in vivo118,218.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The injected lesions showed an increase in OX40L expression and enhanced T cell activation after mRNA-2416.

    “Moreover, the injected lesions showed an increase in OX40L expression and enhanced T cell activation214.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipid nanoparticle-mRNA formulations have been investigated for ex vivo engineering of CAR T cells and for the production of antibodies, such as anti-CD20, anti-human epidermal growth factor receptor 2 and anti-CD3/claudin 6.

    “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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [95] Rybakova, Y. et al. mRNA delivery for therapeutic anti-HER2 antibody expression in vivo. Mol. Ther. 27, 1415–1423 (2019). source

      Not checked in the free run.

    • cites [147] Stadler, C. R. et al. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nat. Med. 23, 815–817 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mRNA-2752 was designed to induce a pro-inflammatory tumour microenvironment and to simultaneously strengthen T cell expansion, as well as memory responses.

    “mRNA-2752 was designed to induce a pro-inflammatory tumour microenvironment and to simultaneously strengthen T cell expansion, as well as memory responses215,216.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Excessive accumulation of metabolites results in clinical symptoms and may lead to death.

    “The excessive accumulation of metabolites then results in clinical symptoms and may lead to death12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mRNA-based protein replacement therapies are also being explored for heart, liver, lung and other organ diseases.

    “mRNA-based protein replacement therapies are also being explored for heart241, liver242, lung243 and other organ diseases12.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [241] Magadum, A., Kaur, K. & Zangi, L. mRNA-based protein replacement therapy for the heart. Mol. Ther. 27, 785–793 (2019). source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    A variety of lipid nanoparticles have been explored and optimized for mRNA delivery, providing valuable information for the future design of mRNA therapeutics.

    “A variety of lipid nanoparticles have been explored and optimized for mRNA delivery, providing valuable information for the future design of mRNA therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MRT5005 was well tolerated at the 8-mg and 16-mg dose levels, and no serious side events were observed at any dose level.

    “MRT5005 was well tolerated at the 8-mg and 16-mg dose levels, and no serious side events were observed at any dose level.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites NCT03375047

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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 cells.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Circular RNA lacks the free ends necessary for nuclease-mediated degradation and therefore has a longer half-life than its linear mRNA counterpart.

    “circRNA lacks the free ends necessary for nuclease-mediated degradation and, therefore, has a longer half-life than its linear mRNA counterpart245,246.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Polymers such as polyethyleneimine, protamine and polyaspartamide derivatives are already widely used for mRNA delivery.

    “Polymers, such as polyethyleneimine, protamine and polyaspartamide derivatives, are already widely used for mRNA delivery7–17.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [10] Li, B., Zhang, X. & Dong, Y. Nanoscale platforms for messenger RNA delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1530 (2019).

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [13] Uchida, S., Perche, F., Pichon, C. & Cabral, H. Nanomedicine-based approaches for mRNA delivery. Mol. Pharm. 17, 3654–3684 (2020). source

      Not checked in the free run.

    • cites [14] Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2021). source

      Not checked in the free run.

    • cites [15] Gebre, M. S. et al. Novel approaches for vaccine development. Cell 184, 1589–1603 (2021). source

      Not checked in the free run.

    • cites [16] Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sequences of these mRNA structural elements regulate translation initiation, translation termination and post-transcriptional modification of mRNA molecules.

    “The sequences of these elements regulate translation initiation, translation termination and post-transcriptional modification of mRNA molecules2,4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    Charge-altering releasable transporters and modified dendrimers can effectively deliver mRNA molecules in vitro and in vivo.

    “In addition, charge-altering releasable transporters162,247 and modified dendrimers248 can effectively deliver mRNA molecules in vitro and in vivo.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Biodegradable lipids enable fast elimination of lipid nanoparticles from plasma and tissues, improving their safety and tolerability.

    “Biodegradable lipids enable fast elimination of lipid nanoparticles from plasma and tissues, improving their safety and tolerability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Biodegradable lipids are part of the mRNA-1273 and BNT162b2 COVID-19 mRNA vaccines.

    “Notably, biodegradable lipids are part of the mRNA-1273 and BNT162b2 COVID-19 mRNA vaccines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    mRNA has shown great therapeutic potential in a number of clinical trials and in clinical applications.

    “In summary, mRNA has shown great therapeutic potential in a number of clinical trials and in clinical applications.”
    Quote in the paperNot a substantial claim
67 of 67

  • 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.”
5 of 5

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?

  • LNP mRNA complexes have excellent biocompatibility and can transfect a variety of tissues and organs.

    “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]

    The Overcoming physiological barriers section describes LNP–mRNA delivery to different cells and organs, including the spleen and lung. But the Safety profiles section does not establish excellent biocompatibility as a general property: it discusses immune activation, cytotoxicity and reported liver and lung injuries in rodents, as well as ways to improve biocompatibility. Page numbers are not available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The ionizable lipid is a major determinant of intracellular delivery by both directly complexing with mRNA and facilitating endosomal escape, while cholesterol provides stability and enables membrane fusion, DOPE supplies structural support, and PEG reduces aggregation and non-specific endocytosis.

    “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]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • LNPs have an ionizable lipid that is predominantly neutral at physiological pH, unlike the quaternary lipid DOTMA, allowing an excellent combination of in vivo efficacy and low toxicity.

    “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 low response to immunotherapy in breast cancer may be related to the immunosuppressive tumor microenvironment.

    “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]

    The Cancer section discusses inducing a pro-inflammatory tumour microenvironment with mRNA formulations, but does not link an immunosuppressive microenvironment to low immunotherapy response in breast cancer. Searches for breast cancer, immunosuppression, and treatment response found no passage making that connection. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • 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.

    “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.

  • Reference 223 is cited for a different disorder

    Minor

    The text cites reference 223 for acute intermittent porphyria, but the reference list identifies it as a study of alpha 1-antitrypsin deficiency.

1 of 1

Cites

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4 of the 259 references couldn’t be matched to a known paper.

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Related

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
ORCID
Venue
Nature Reviews Materials
Publisher
Springer Science and Business Media LLC
Published
2021-08-10
Volume
6
Issue
12
Pages
1078-1094
ISSN
2058-8437 (ISSN-L)
DOI
10.1038/s41578-021-00358-0
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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