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Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines
Open accessAbstract
mRNA vaccines have the potential to tackle many unmet medical needs that are unable to be addressed with conventional vaccine technologies. A potent and well-tolerated delivery technology is integral to fully realizing the potential of mRNA vaccines. Pre-clinical and clinical studies have demonstrated that mRNA delivered intramuscularly (IM) with first-generation lipid nanoparticles (LNPs) generates robust immune responses. Despite progress made over the past several years, there remains significant opportunity for improvement, as the most advanced LNPs were designed for intravenous (IV) delivery of siRNA to the liver. Here, we screened a panel of proprietary biodegradable ionizable lipids for both expression and immunogenicity in a rodent model when administered IM. A subset of compounds was selected and further evaluated for tolerability, immunogenicity, and expression in rodents and non-human primates (NHPs). A lead formulation was identified that yielded a robust immune response with improved tolerability. More importantly for vaccines, increased innate immune stimulation driven by LNPs does not equate to increased immunogenicity, illustrating that mRNA vaccine tolerability can be improved without affecting potency.
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In the citing paper
“which are known to have significantly higher delivery efficiency in hepatocytes after intravenous (i.v.) injection31 or in muscle cells after intramuscular (i.m.) injection.32”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [32]
In the citing paper
“Based on these observations, Moderna has developed an ionizable lipid (namely Lipid H, SM-102), whose tail adopts larger branches which in turn increases potency, and whose introduced ester bonds increase biodegradability (Fig. 7).290,291”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [291]
In the citing paper
“All three major players in the mRNA vaccine field have previously optimized so-called lipid nanoparticles (LNPs), constructs that typically consist of an ionizable lipid and one or more helper lipids to improve LNP stability and promote endosomal escape upon cellular uptake [12,13]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [13]
In the citing paper
“For Moderna's LNP formulation, Hassett et al. reported that the SM-102 lipid was selected based on its improved tolerability profile in non-human primates, as evidenced by a reduced local reactogenicity (e.g., edema and erythema) and lowest induction of systemic cytokine responses (e.g., IL-6) [13]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [13]
In the citing paper
“the usage of the SM-102 lipid in Moderna's mRNA-1273 vaccine was found to outperform Onpattro's MC3 LNPs for the intramuscular (i.m.) delivery of mRNA in rodents and non-human primates, given its improved tolerability and higher endosomal escape efficiency [12,13]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [13]
In the citing paper
“Endosomal escape can be increased by optimizing the pKa values of ionizable lipids66,76–78,88,100,140.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [78]
In the citing paper
“To improve the biocompatibility of lipid nanoparticles, biodegradable lipids can be applied76–78,108,179.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [78]
In the citing paper
“Moreover, the delivery efficacy of mRNA could be improved, for example, by rational design of lipids through modulation of head groups and hydrophobic tails to increase cellular uptake and endosomal escape of lipid nanoparticle–mRNA formulations64,66,76–78,88,97,100,114,140,141.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [78]
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Metadata
- Authors
- Hassett, K. J., Benenato, K. E., Jacquinet, E., Lee, A., Woods, A., Yuzhakov, O., Himansu, S., Deterling, J., Geilich, B. M., Ketova, T., Mihai, C., Lynn, A., McFadyen, I., Moore, M. J., Senn, J. J., Stanton, M. G., Almarsson, Ö., Ciaramella, G., & Brito, L. A.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Corresponding author
- Brito, Luis A.
- ORCID
- Venue
- Molecular Therapy — Nucleic Acids
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 15
- Pages
- 1-11
- ISSN
- 2162-2531 (ISSN-L)
- PMC
- PMC6383180
- OpenAlex
- W2914060533
- Cited by
- 927
- References
- 35
- Citations by year
- 2026: 141 · 2025: 202 · 2024: 162 · 2023: 140 · 2022: 128 · 2021: 114 · 2020: 35 · 2019: 5
- FWCI
- 23.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (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
- Moderna Therapeutics
- 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
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- lipid nanoparticles, mRNA vaccines, intramuscular administration, ionizable lipids, biodegradable lipids, immunogenicity, tolerability, innate immune activation, non-human primates
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