The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory
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Abstract
Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against COVID-19. Clinical trials and ongoing vaccinations present with varying degrees of protection levels and side effects. However, the drivers of the reported side effects remain poorly defined. Here we present evidence that Acuitas' LNPs used in preclinical nucleoside-modified mRNA vaccine studies are highly inflammatory in mice. Intradermal and intramuscular injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate, with mechanism unresolved. Thus, the mRNA-LNP platforms' potency in supporting the induction of adaptive immune responses and the observed side effects may stem from the LNPs' highly inflammatory nature.
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saRNA can address shortcomings of mRNA by decreasing the number of doses and administration frequency, mitigating side effects and bolstering manufacturing capacity.
“saRNA can address the shortcomings of mRNA by decreasing the number of doses and the administration frequency, which will mitigate side effects8–10 and bolster manufacturing capacity”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [9]
The Discussion (page unavailable) says side effects after a second mRNA-LNP vaccination could be further exacerbated, which lends some support to the idea that fewer administrations might reduce side effects. It does not discuss saRNA or establish that saRNA requires fewer doses or mitigates side effects; the manufacturing-capacity claim is also unsupported by this source. (LLM, conf=0.78)
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Trougakos, I. P., Terpos, E., Alexopoulos, H., Politou, M., Paraskevis, D., Scorilas, A., Kastritis, E., Andreakos, E., & Dimopoulos, M. A. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.04.007 · Cited by 273 · see citing works
Padín-González, E., Lancaster, P., Bottini, M., Gasco, P., Tran, L., Fadeel, B., Wilkins, T., & Monopoli, M. P. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.882363 · Cited by 166 · see citing works
Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity
Tsai, S. J., Atai, N. A., Cacciottolo, M., Nice, J., Salehi, A., Guo, C., Sedgwick, A., Kanagavelu, S., & Gould, S. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101266 · Cited by 142 · see citing works
McGee, J. E., Kirsch, J. R., Kenney, D., Cerbo, F., Chavez, E. C., Shih, T.-Y., Douam, F., Wong, W. W., & Grinstaff, M. W. (2025) · Nature Biotechnology · doi:10.1038/s41587-024-02306-z · Cited by 87 · see citing works
Sugimoto, Y., Suga, T., Umino, M., Yamayoshi, A., Mukai, H., & Kawakami, S. (2023) · Drug Delivery · doi:10.1080/10717544.2023.2191891 · Cited by 19 · see citing works
- Authors
- Ndeupen, S., Qin, Z., Jacobsen, S., Bouteau, A., Estanbouli, H., & Igyártó, B. Z.
- Affiliations
- Thomas Jefferson University (US)
- Corresponding author
- Igyártó, Botond Z.
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 24
- Issue
- 12
- Pages
- 103479
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC8604799
- OpenAlex
- W3217355073
- Cited by
- 678
- References
- 82
- Citations by year
- 2026: 145 · 2025: 172 · 2024: 137 · 2023: 114 · 2022: 90 · 2021: 20
- FWCI
- 28.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NIAID
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- mRNA-LNP vaccine, lipid nanoparticles, vaccine adjuvants, inflammation, vaccine side effects, neutrophil infiltration, inflammatory cytokines, chemokines, intranasal drug delivery, lung inflammation, mRNA vaccines, COVID-19 vaccines, nucleoside-modified mRNA
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