The DOI matches its Crossref record; 82 of the 85 references it cites were found in a registry or an index; 2 of the 84 sources its claims cite were checked for support.
mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability
Open accessAbstract
A drawback of the current mRNA-lipid nanoparticle (LNP) COVID-19 vaccines is that they have to be stored at (ultra)low temperatures. Understanding the root cause of the instability of these vaccines may help to rationally improve mRNA-LNP product stability and thereby ease the temperature conditions for storage. In this review we discuss proposed structures of mRNA-LNPs, factors that impact mRNA-LNP stability and strategies to optimize mRNA-LNP product stability. Analysis of mRNA-LNP structures reveals that mRNA, the ionizable cationic lipid and water are present in the LNP core. The neutral helper lipids are mainly positioned in the outer, encapsulating, wall. mRNA hydrolysis is the determining factor for mRNA-LNP instability. It is currently unclear how water in the LNP core interacts with the mRNA and to what extent the degradation prone sites of mRNA are protected through a coat of ionizable cationic lipids. To improve the stability of mRNA-LNP vaccines, optimization of the mRNA nucleotide composition should be prioritized. Secondly, a better understanding of the milieu the mRNA is exposed to in the core of LNPs may help to rationalize adjustments to the LNP structure to preserve mRNA integrity. Moreover, drying techniques, such as lyophilization, are promising options still to be explored.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This review synthesizes the structure and storage stability of mRNA-LNP COVID-19 vaccines, concluding that mRNA exposure to water is likely the main driver of instability and that frozen storage remains necessary. It outlines analytical methods and stabilization opportunities such as excipient optimization and lyophilization, while highlighting major gaps in public stability data.
Key findings
- Current mRNA-LNP COVID-19 vaccines require frozen storage: Moderna’s vaccine is kept at −15 to −25 °C and Pfizer/BioNTech’s at −60 to −90 °C; at 2–8 °C, Pfizer/BioNTech and Moderna vaccines are stable for 5 and 30 days, respectively, while CureVac’s candidate is reported stable for 3 months at refrigerator temperatures and at −60 °C.
- mRNA instability, rather than LNP instability, likely dictates storage conditions: siRNA-LNP Onpattro has a 3-year shelf life at 2–8 °C, and siRNA-LNPs remained stable at 2 °C for 156 days at pH 7 and at 4 °C for 1.5 years, whereas naked mRNA in aqueous solution can be stored at 4 °C for only a few days with RNase protection.
- mRNA-LNPs are about 60–100 nm, with examples nCoVsaRNA at 75 nm and ARCoV at 89 nm; encapsulation efficiencies are typically >90%, and the isotropic LNP core may contain 24% water by volume fraction, potentially exposing mRNA to water and hydrolysis.
- mRNA engineering includes 1-methyl-pseudouridine (m1Ψ) in Moderna and Pfizer/BioNTech vaccines and GC-enrichment in CureVac; conventional mRNA vaccines use 30 µg (Pfizer/BioNTech), 100 µg (Moderna), and 12 µg (CureVac) intramuscular doses, while self-amplifying mRNA constructs are about 9 kb versus 2–4 kb for non-replicating mRNA.
Methods
- Narrative review; no primary experiments or new data are reported.
- Draws on published literature, product and regulatory documents, and tables comparing BNT162b2/Comirnaty, mRNA-1273, CVnCoV, Onpattro, and self-amplifying mRNA candidates.
- Synthesizes proposed mRNA-LNP structural models from cryo-TEM, SAXS/SANS, and NMR, mRNA degradation chemistry, analytical assays, and storage-stability evidence.
Limitations
- Stated: little public data exist on long-term storage of mRNA-LNP formulations, the extent to which encapsulation affects storage stability is unclear, and very little is known about LNP structure/morphology, chemical stability of LNP components, and colloidal stability of the mRNA-LNP system.
- Stated: no research report was available in the public domain on the integrity of both mRNA and LNPs in mRNA-LNP formulations, and questions remain about mRNA-LNP structure and mRNA–lipid interactions.
- Evident: as a review, it relies on indirect evidence from siRNA-LNPs, naked mRNA, and product/regulatory documents rather than controlled head-to-head stability studies; some quality information comes from leaked EMA documents and public summaries rather than full public specifications.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
60 Not checked yet · 26 Own interpretation · 10 No basis given · 1 Partly supported · accuracy not yet measured
In the paper
“The 2′ OH group on the ribose plays a crucial role as the transesterification reaction leading to a mRNA strand break starts by a nucleophilic attack by the 2′OH group on the phosphate ester bond leading to a break at the P-O5′ ester bond (Fig. 5).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Pogocki and Schöneich, 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In two publications on mRNA hydrolysis the authors state that the base sequence and secondary structure of mRNA influence the rate of hydrolysis (Kaukinen et al., 2002, Mikkola et al., 2001).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hydrolysis predominantly occurs via the phosphodiester bonds that form the backbone of the mRNA molecule (Fig. 5 ).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Pogocki and Schöneich, 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, base-stacking may decrease the cleavage rate of phosphodiester bonds.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
hedgedconditional- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Chemical degradation of mRNA in vitro mainly occurs through hydrolysis and oxidation.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Houseley and Tollervey, 2009
- Not checked yetcites Pogocki and Schöneich, 2000
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.
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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
“The composition of the Onpattro LNP system is: DLin-MC3-DMA, as ionizable cationic lipid: DSPC: cholesterol: PEG2000-C-DMG (see table 1) (mol-ratio 50:10:38.5:1.5 mol%); they are composition-wise similar to the LNPs in Comirnaty and mRNA-1273.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
plain- 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
“The carboxylic ester bonds in lipids, such as DSPC and the ionizable cationic lipids, are susceptible to temperature- and pH-dependent hydrolysis (Fig. 6 ).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In 2009, Roesler et al. show that the translation efficacy of mRNA encoding luciferase begins to decrease after 8 days or 16 days when stored –RNAse free– at room temperature as a liquid or in a lyophilized form, respectively.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Which mRNA-LNP component is more unstable: The mRNA, the lipids, or the combination?
What the sources say
- Not checked yetcites Roesler et al., 2009 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.
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In the paper
“Oxidation, in contrast, affects the nucleobases and to a lesser extent the sugar groups of the mRNA's ribose units.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Pogocki and Schöneich, 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In their review Pascolo et al. remark that aqueous solutions of naked mRNA can be stored at 4 °C for only a few days, provided that the mRNA is protected from degradation by contaminating ribonucleases by an RNase inhibitor (Pascolo, 2008).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Which mRNA-LNP component is more unstable: The mRNA, the lipids, or the combination?
What the sources say
- Not checked yetcites Pascolo, 2008
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.
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- Probably not a substantial claim. 10
- It may state two separate claims as one. 27
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Other researchers propose that the outer shell of mRNA-LNPs consists of one or multiple bilayers, based on cryo-TEM analysis (Fig. 2) (Patel et al., 2020, Tanaka et al., 2020) or SANS (Sebastiani et al., 2021).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Partly supportedcites Patel et al., 2020 sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports that cryo-TEM shows a lamellar structure on the particle surface, supporting the proposed bilayer-like outer shell. It also describes single- and multilamellar arrangements, but that passage concerns mRNA organization and does not establish that the outer shell itself consists of one or multiple bilayers. (LLM, conf=0.82)
- Not checked yetcites Tanaka et al., 2020 source
- Supportedcites Sebastiani et al., 2021 source
In Results and Discussion, under “Determination of Structure and Composition in the Core and Shell of mRNA-LNPs,” the SANS analysis supports a single-shell model. The measured shell thickness is closer to a DSPC bilayer than a monolayer, leading the authors to suggest that a disordered bilayer probably forms. This supports the cited paper as evidence for the one-bilayer possibility, not for multiple bilayers. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“This process requires water and can be catalyzed by nucleases, but also by the mRNA molecule itself and other exogenous factors like Brønsted acids and bases (Houseley and Tollervey, 2009, Pogocki and Schöneich, 2000).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Houseley and Tollervey, 2009
- Not checked yetcites Pogocki and Schöneich, 2000
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.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aggregation of LNPs during storage and fusion of LNPs has been reported (Ayat et al., 2019, Ball et al., 2016).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Wayment-Steele et al. predict that mRNA (4000 nt) will have a half-life of 941 days when it is stored at pH 7.4 and 5 °C (Wayment-Steele et al., 2020).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Which mRNA-LNP component is more unstable: The mRNA, the lipids, or the combination?
What the sources say
- Not checked yetcites Wayment-Steele et al., 2020
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Introduction of polysarcosine-modified lipids stabilized lipid-based systems against aggregation while reducing the immunostimulatory response (Nogueira et al., 2020).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
What the sources say
- Not checked yetcites Nogueira et al., 2020 source
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“pH optimization is also important for mRNA vaccine stability, as the pH influences the hydrolysis rate of mRNA and also LNP stability.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Opportunities for improving shelf life & storage conditions > Excipients
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: mRNA is most stable in a weakly basic environment.
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
“mRNA that is not encapsulated (‘naked mRNA’) is hardly taken up by cells; besides, it degrades rapidly and is, therefore, not available for translation.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Oxidation can lead to the cleavage of bases, strand break and the alteration of the secondary structure of the mRNA (Pogocki and Schöneich, 2000).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Pogocki and Schöneich, 2000
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.
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It may state two separate claims as one.
In the paper
“They do note that longer mRNA sequences, such as SAMs, are more prone to hydrolysis.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Which mRNA-LNP component is more unstable: The mRNA, the lipids, or the combination?
What the sources say
- Not checked yetcites Wayment-Steele et al., 2020
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
“Lipid oxidation can occur in unsaturated fatty acid moieties (not present in Comirnaty and mRNA-1273) and with cholesterol, potentially as a result of a hydroperoxide attack, an impurity present in the PEG-group of PEG2000-C-DMG (Jaeger et al., 1994, Wang et al., 2019).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
What the sources say
hedgedconditional- 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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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, denaturation also comprises processes such as aggregation and precipitation, which negatively affect mRNA translation.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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.
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
“Of note, encapsulation efficiencies are typically > 90% and release of the RNA payload from LNPs during storage has not been reported (as measured with the RiboGreen test).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > LNP stability
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Contrary to the data on siRNA-LNPs obtained by Shirane et al., they found that after lyophilization and reconstitution the in vitro test showed no loss of activity, but the in vivo efficiency was lost.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Opportunities for improving shelf life & storage conditions > Lyophilization
What the sources say
- Not checked yetcites Zhao et al., 2020
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The latter contains positively charged ionizable amine groups (at low pH) to interact with the anionic mRNA during particle formation and also facilitate membrane fusion during internalization (Evers et al., 2018, Reichmuth et al., 2016).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
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 is hydrophilic; it can interact electrostatically and through hydrogen bonds with ionizable cationic lipids (apparent pKa < 6.5) (Buschmann et al., 2021).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Buschmann et al., 2021 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.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In mRNA-LNP formulations, such as those used in mRNA vaccines, the fraction of accessible mRNA is very low (Yanez Arteta et al., 2018, Patel et al., 2020) and thus, encapsulation efficiencies, derived from RiboGreen assays, are typically > 90%.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
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
“Inside the core, the main part of the ionizable cationic lipid, cholesterol (dependent on its concentration), water and mRNA are present.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Yanez Arteta et al., 2018 source
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.
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 multilamellar vesicle model for mRNA-LNPs (Fig. 3A) is unlikely to be correct. It does not correspond to the electron dense cores found by TEM of the mRNA-LNPs.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
hedgeddirect- 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
“Besides, there are indications that mRNA is located in the core of the LNPs and siRNA more towards the surface and mRNA can form ‘blebs’ (Fig. 2) (Viger-Gravel et al., 2018).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Viger-Gravel et al., 2018 source
hedgedcorrelational- 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
“This would mean that the mRNA is –at least partly– exposed to water inside the LNPs, which likely contributes to its instability upon storage under non-frozen conditions (Arteta et al., 2018).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Arteta et al., 2018 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.
In the paper
“mRNA is at least 100-fold larger than siRNA and this affects the structure of the LNPs.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Table 2
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.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A key aspect of LNPs and the characteristic that makes them different from liposomes (spherical vesicles with at least one lipid bilayer and an aqueous core) is the presence of lipids in the core, although data from several studies indicate that water is also present to some extent (Yanez Arteta et al., 2018, Kulkarni et al., 2018, Brader et al., 2021).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
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
“Analysis of the components of the various mRNA-COVID-19 vaccines has shown that there are common features, but also significant differences (Table 1).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
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: 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
“For siRNA only weak electrostatic interactions were found with the ionizable cationic lipid, indicating that at least for siRNA-LNP formulations the pH inside approaches or equals the pH outside (Viger-Gravel et al., 2018).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
- Not checked yetcites Viger-Gravel et al., 2018 source
hedged- 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
“This, in turn, could have implications for the stability of different formulations.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Another interesting finding by Arteta et al. is that the shell of their mRNA-LNPs is a monolayer (Yanez Arteta et al., 2018, Verbeke et al., 2019).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
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.
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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
“The LNP formulation, the use of modified-nucleosides, the GC content and the differences in length between the conventional mRNA and SAM vaccines might influence the physical and chemical stability of these mRNA-COVID-19 vaccines during storage.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
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.
- Rests on an assumption: The composition of mRNA-LNP vaccines is fundamental to their stability.
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
“These findings indicate that assessment of the nature of the mRNA-LNP shell with these techniques is difficult and/or that multiple types of mRNA-LNP structures may exist, dependent on, e.g., the nature of the lipids and the preparation protocol for the mRNA-LNPs.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
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
“Consequently, for mRNA vaccines, it is critical to monitor the integrity of the full molecule.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence.
None of the sources cited for this claim have been checked yet.
In the paper
“If the LNP shells are permeable to protons –which is likely, as ionized dyes such as 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) and thionine can enter the LNP core (Jayaraman et al., 2012, Brader et al., 2021) – the pH would be similar to the rest of the formulation, around 7 to 8, meaning that most of the ionizable cationic lipids would be uncharged.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Overview of mRNA vaccines > LNPs as delivery system
What the sources say
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.
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
“This would mean that the mRNA is in an aqueous environment and therefore is susceptible to hydrolysis.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Which mRNA-LNP component is more unstable: The mRNA, the lipids, or the combination?
hedgeddirect- 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
“As the presence of water initiates degradation reactions in mRNA-LNPs, lyophilization would be a logical step to improve the long-term stability of mRNA-LNP formulations.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Opportunities for improving shelf life & storage conditions > Lyophilization
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence.
- Rests on an assumption: The presence of water initiates degradation reactions in mRNA-LNPs.
In the paper
“In a review on the stability of nucleic acids Pogocki and Schöneich state that chemical degradation plays a larger role in the degradation of small nucleic acids than physical instability and that is probably even more true for large structures such as mRNA (Pogocki and Schöneich, 2000).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > mRNA stability
What the sources say
- Not checked yetcites Pogocki and Schöneich, 2000
hedgeddirect- 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.
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
“An implication of this is that decreasing the exposure to water would be a promising approach for improving mRNA vaccine stability.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Conclusions and prospects
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence.
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, the studies with either mRNA or with LNPs suggest that lyophilization could be a possible way to increase the stability of the combination, mRNA-LNP, and could thereby allow for storage at higher temperatures than those currently required.”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Opportunities for improving shelf life & storage conditions > Lyophilization
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.
- Rests on an assumption: The presence of water initiates degradation reactions in mRNA-LNPs.
The paper relies on this without support.
Currently, hardly any data is available in the public domain on what happens when mRNA-LNP formulations are stored for long periods of time.
“Currently, hardly any data is available in the public domain on what happens when mRNA-LNP formulations are stored for long periods of time.”
The paper relies on this without support.
It is unclear to what extent entrapping mRNA within LNPs influences the storage stability of the mRNA vaccine.
“Moreover, it is unclear to what extent entrapping mRNA within LNPs influences the storage stability of the mRNA vaccine.”
The paper relies on this without support.
Very little is known about the structure and morphology of LNPs formulated with mRNA, the chemical stability of the LNP components and the colloidal stability of the mRNA-LNP system.
“Additionally, very little is known about the structure and morphology of LNPs formulated with mRNA, the chemical stability of the LNP components and the colloidal stability of the mRNA-LNP system.”
The paper relies on this without support.
The degradation processes and the reasons why storage temperature requirements differ are not fully understood.
“To date, the degradation processes and the reasons why storage temperature requirements differ, are not fully understood.”
The paper relies on this without support.
The composition of mRNA-LNP vaccines is fundamental to their stability.
“The composition of mRNA-LNP vaccines is fundamental to their stability.”
The paper relies on this without support.
PEG-lipid is used to control the particle size and act as a steric barrier to prevent aggregation during storage.
“In addition, PEG-lipid is used to control the particle size and act as a steric barrier to prevent aggregation during storage.”
The paper relies on this without support.
One factor that strongly influences the required storage conditions is the stability of the mRNA.
“One factor that strongly influences the required storage conditions is the stability of the mRNA.”
The paper relies on this without support.
The integrity and purity of the mRNA are essential to safeguard efficacy and safety of mRNA vaccines.
“As the integrity and purity of the mRNA are essential to safeguard efficacy and safety of mRNA vaccines, it is important to have tools to monitor these aspects.”
The paper relies on this without support.
No information on LNP stability tests is available for the present mRNA COVID-19 vaccines.
“No information on LNP stability tests could be found for the present mRNA COVID-19 vaccines, but the siRNA-LNP formulation of Onpattro (patisaran) has a three-year shelf life when kept between 2° and 8 °C (EMA, 2018).”
The paper relies on this without support.
There is no research report available in the public domain on the integrity of both mRNA and LNPs in mRNA-LNP formulations.
“To date, there is no research report available in the public domain on the integrity of both mRNA and LNPs in mRNA-LNP formulations.”
The paper relies on this without support.
The presence of water initiates degradation reactions in mRNA-LNPs.
“As the presence of water initiates degradation reactions in mRNA-LNPs, lyophilization would be a logical step to improve the long-term stability of mRNA-LNP formulations.”
The paper relies on this without support.
mRNA is most stable in a weakly basic environment.
“Generally, mRNA is most stable in a weakly basic environment.”
The paper relies on this without support.
Quality specifications for the presently accepted mRNA-LNP COVID-19 products are still not available in the public domain.
“Quality specifications for the presently accepted mRNA-LNP COVID-19 products are still not available in the public domain.”
The paper relies on this without support.
Lyophilization of mRNA-LNP faces hurdles including high energy consumption and costs related to expanding lyophilization capacity.
“Apart from challenges to preserve the integrity of mRNA-LNP through lyophilization, there are other hurdles such as the high energy consumption of the process and other costs, e.g., those related to the necessary, dramatic expansion of the lyophilization capacity worldwide in times of a pandemic.”
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
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > Introduction
“The current mRNA COVID-19 vaccines of Moderna and BioNTech/Pfizer have to be kept between −15 and −25 °C and between −60 and −90 °C, respectively (EMA, 2020a, EMA, 2021).”
§ mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability > In vitro stability of mRNA vaccines > Reasons for different storage conditions
“the Pfizer/BioNTech mRNA-LNP vaccine, that currently has to be stored between −60 to −80 °C”
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Polyphenolic Nanoparticle Platforms (PARCELs) for In Vitro and In Vivo mRNA Delivery
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Optimizing mRNA-Loaded Lipid Nanoparticles as a Potential Tool for Protein-Replacement Therapy
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Nanotechnology-Enabled COVID-19 mRNA Vaccines
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A self-adjuvanted VLPs-based Covid-19 vaccine proven versatile, safe, and highly protective
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Inhaled non-viral delivery systems for RNA therapeutics
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Lipid-Polyhydroxyalkanoate Hybrid Nanoparticles as Sustainable Platform for mRNA delivery
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Edmonds, K. K., Wilkinson, M. E., Strebinger, D., Chen, H., Lash, B., Schaefer, C. C., Zhu, S., Liu, D., Zilberzwige‐Tal, S., Ladha, A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-61321-z · Cited by 17
Innovative nanocarriers: Synthetic and biomimetic strategies for enhanced drug delivery
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Towards clinical translation of nanomedicines: Formulation scale-up and model systems
Kelly, O. M., Hanna, A. R., Byrne, A. K., Green, J. A., Périssé, I. V., Wells, K. D., Murray, S. A., Xu, J., Chen, Y. E., Polejaeva, I. A., et al. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115862 · Cited by 20
Selmin, F., Musazzi, U. M., Franzè, S., Scarpa, E., Rizzello, L., Procacci, P., & Minghetti, P. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13071029 · Cited by 17
Detection, prevention and treatment of COVID‐19 and opportunities for nanobiotechnology
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Think like a Virus: Toward Improving Nanovaccine Development against SARS-CoV-2
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Sugito, N., Heishima, K., & Akao, Y. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.09.001 · Cited by 17
Licensed liposomal vaccines and adjuvants in the antigen delivery system
Krasnopolsky, Y., & Pylypenko, D. (2022) · Biotechnologia · doi:10.5114/bta.2022.120709 · Cited by 21
Di, J., Hou, P., Corpstein, C. D., Wu, K., Xu, Y., & Li, T. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.05.048 · Cited by 17
Messerian, K. O., Zverev, A., Kramarczyk, J. F., & Zydney, A. L. (2023) · Journal of Membrane Science · doi:10.1016/j.memsci.2023.121896 · Cited by 17
MicroRNA137-loaded lipid nanoparticles regulate synaptic proteins in the prefrontal cortex
Palumbo, M., Gautam, M., Sonneborn, A., Kim, K., Wilmarth, P. A., Reddy, A. P., Shi, X., Marks, D. L., Sahay, G., Abbas, A. I., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.08.016 · Cited by 23
Xu, Y., Hu, Y., Xia, H., Zhang, S., Lei, H., Yan, B., Xiao, Z. X., Chen, J., Pang, J., & Zha, G. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202302691 · Cited by 18
mRNA extraction from lipid nanoparticles
Malburet, C., Carboni, A., Guinamand, S., Naik, H., & Fertier-Prizzon, S. (2023) · Journal of Chromatography A · doi:10.1016/j.chroma.2023.464545 · Cited by 17
Jalil, S., Keskinen, T., Juutila, J., Sartori-Maldonado, R., Euro, L., Suomalainen, A., Lapatto, R., Kuuluvainen, E., Hietakangas, V., Otonkoski, T., et al. (2024) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.03.004 · Cited by 18
NANOSPRESSO: toward personalized, locally produced nucleic acid nanomedicines
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Can pulmonary RNA delivery improve our pandemic preparedness?
Merkel, O. M. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.039 · Cited by 17
The Binding Affinities of Serum Proteins to Nanoparticles
Stordy, B. P., Sepahi, Z., Patrón, G. D., Yang, W., Goodson, A., Blackadar, C., Tavares, A. J., Lin, G., Malekjahani, A., Ling, B., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c02576 · Cited by 16
Mechanistic modeling of lipid nanoparticle formation for the delivery of nucleic acid therapeutics
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Estabrook, D. A., Huang, L., Lucchese, O. R., Charland, D. J., Zhao, Y. R., Sayyed, F. B., Buser, J. Y., Oh, Y., Liu, X., Johnson, H. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63651-4 · Cited by 16
Therapeutic peptides and proteins: Status and developments in drug delivery
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Kapnick, S. M. (2021) · DNA and Cell Biology · doi:10.1089/dna.2021.0538 · Cited by 16
Verleye, A., Wijtvliet, V. P. W. M., Abrams, S., Hellemans, R., Bougrea, R., Massart, A., Pipeleers, L., Wissing, K. M., Ariën, K. K., Winter, B. Y. D., et al. (2022) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfac174 · Cited by 17
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Nanoparticles of VAV1 siRNA combined with LL37 peptide for the treatment of pancreatic cancer
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The global patent landscape of mRNA for diagnosis and therapy
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Lipid nanoparticles-based RNA therapies for breast cancer treatment
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Advancement in the development of mRNA ‐based vaccines for respiratory viruses
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Nano Plasma Membrane Vesicle‐Lipid Nanoparticle Hybrids for Enhanced Gene Delivery and Expression
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Circular mRNA Vaccine against SARS-COV-2 Variants Enabled by Degradable Lipid Nanoparticles
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Metadata
- Authors
- Schoenmaker, L., Witzigmann, D., Kulkarni, J. A., Verbeke, R., Kersten, G., Jiskoot, W., & Crommelin, D. J. A.
- Affiliations
- Leiden University (NL)
- University of British Columbia (CA)
- Ghent University (BE)
- Utrecht University (NL)
- Corresponding author
- Jiskoot, Wim
- Crommelin, Daan J.A.
- ORCID
- Venue
- International Journal of Pharmaceutics
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 601
- Pages
- 120586
- ISSN
- 0378-5173 (ISSN-L)
- PMC
- PMC8032477
- OpenAlex
- W3148255637
- Cited by
- 1,566
- References
- 85
- Citations by year
- 2026: 267 · 2025: 351 · 2024: 317 · 2023: 291 · 2022: 259 · 2021: 81
- FWCI
- 24.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- International Journal of Pharmaceutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Universiteit Leiden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- COVID-19 vaccines, vaccine stability, ionizable cationic lipids, helper lipids, mRNA degradation, freeze-drying
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, Humans, Lipids, RNA, Messenger, RNA, Small Interfering, Nanoparticles
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.
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