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A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates
Open accessAbstract
The success of mRNA-based therapies depends on the availability of a safe and efficient delivery vehicle. Lipid nanoparticles have been identified as a viable option. However, there are concerns whether an acceptable tolerability profile for chronic dosing can be achieved. The efficiency and tolerability of lipid nanoparticles has been attributed to the amino lipid. Therefore, we developed a new series of amino lipids that address this concern. Clear structure-activity relationships were developed that resulted in a new amino lipid that affords efficient mRNA delivery in rodent and primate models with optimal pharmacokinetics. A 1-month toxicology evaluation in rat and non-human primate demonstrated no adverse events with the new lipid nanoparticle system. Mechanistic studies demonstrate that the improved efficiency can be attributed to increased endosomal escape. This effort has resulted in the first example of the ability to safely repeat dose mRNA-containing lipid nanoparticles in non-human primate at therapeutically relevant levels.
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“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 [290]
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 [12]
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 [12]
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 [77]
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 [77]
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 [77]
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“position of LNP [55,56] and size [57] were published.”
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“These nanoparticles are 80–100 nm in diameter [44] and contain about 100 mRNA molecules each [45].”
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Alqahtani, M. S., Syed, R., Alqahtani, A. S., Almarfadi, O. M., Roni, M. A., & Sadhu, S. S. (2024) · Nanoscale Advances · doi:10.1039/d4na00404c · Cited by 8
“18 Biomimetic and bioinspired nanomaterials, such as lipopeptide-based nanoparticles, have gained signi cant attention in recent years, particularly in the eld of drug delivery.”
BackgroundTherapeutic Application of mRNA for Genetic Diseases
Schürmann, P. J. L., Vriesman, S. V. B., Castro-Alpízar, J., Kooijmans, S. A. A., Nieuwenhuis, E. E. S., Schiffelers, R. M., & Fuchs, S. A. (2025) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.70019 · Cited by 9
“The tails can differ in number, length, sidechains, and saturation, thereby affecting LNP fluidity, stability, cellular uptake, and mRNA delivery (Heyes et al. 2005; Sabnis et al. 2018).”
In Silico Study of Ionizable Lipid Nanoparticles Using the SPICA Force Field
Singh, A. P., Tanaka, H., Miyazaki, Y., Nagano, S., & Shinoda, W. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5c00498 · Cited by 8
Lipid Nanoparticle Development for A Fluvid mRNA Vaccine Targeting Seasonal Influenza and SARS-CoV-2
Felgner, J. H., Hernandez‐Davies, J. E., Strahsburger, E., Silzel, E. K., Nakajima, R., Jain, A., Laster, J., Chiang, J.-L., Tsai, Y.-L., Felgner, P. L., et al. (2025) · npj Vaccines · doi:10.1038/s41541-025-01153-6 · Cited by 10
Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells
Li, Z., Ee, A., Amaya, L., Hamad, J. L., Yadav, P. K., Wang, S. K., Chang, H. Y., & Wender, P. A. (2025) · Nature Communications · doi:10.1038/s41467-025-62200-3 · Cited by 8
“Weobservedthatmost top performers have branched lipid tails on both sides of the guanidinium-ester core (lipid # 6-14), consistent with fi ndings from LNP studies that indicate larger lipid volume enhances delivery ef fi ciency 44 .”
Innovative gene engineering and drug delivery systems for dendritic cells in cancer immunotherapy
Prakash, M., Cortez, C. D., Jayaraman, A., Hsu, S.-Y., Huang, Y., Yeh, C.-Y., & Lee, Y. L. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01191-1 · Cited by 9
“LNPs formulated with similar ionizable lipids (i.e., SM-102, cKK-E12, and C12–200) also showed unintended liver tropism [199–201].”
Kunc, M., Whitehead, B. J., Østergaard, L. J., Tolstrup, M., Benn, C. S., Wejse, C. M., & Nejsum, P. L. (2025) · Journal of Clinical Immunology · doi:10.1007/s10875-025-01977-w · Cited by 9
“For instance, Gote [ 62] demonstrated that the proprietary lipids in the mRNA-1273 (SM-102) formulation [63 ] are about three times more efficient at deliv - ering mRNA compared to ALC-0315 used in BNT162b2 [64].”
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Nanoparticle delivery for central nervous system diseases and its clinical application
Tang, L., Zhang, R., Wang, Y., Liu, M., Hu, D., Wang, Y., & Li, Y. (2024) · Nano Research · doi:10.1007/s12274-024-6598-1 · Cited by 8
Unlock the sustained therapeutic efficacy of mRNA
Cao, D., Tian, M., Liu, Z., Guo, K., Peng, J., Ravichandra, A., Ferrell, C., & Dong, Y. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113837 · Cited by 8
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“The effective delivery of mRNAbased vaccines and therapies is enabled by the use of lipid nanoparticles (LNPs), which protect nucleic acid degradation by exo- and endonucleases [11,12] and facilitate cellular uptake and expression [13,14,78], Used in both the Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines, this de…”
mRNA—From COVID-19 Treatment to Cancer Immunotherapy
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“However, structural optimization of ionizable lipids cannot simultaneously enhance both cellular uptake and endosomal escape efficiency of LNPs [12].”
BackgroundResultInfluentialProgress in novel delivery technologies to improve efficacy of therapeutic antibodies
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mRNA-LNP vaccines: rational design, delivery optimization, and clinical translation
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Preparing for Pandemics: RNA Vaccines at the Forefront
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Quantitative biodistribution of nanoparticles in plants with lanthanide complexes
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“Typically, lipid-based nanoparticles are composed of neutral lipids, cholesterol, an ionizable lipid, and a PEGylated lipid 22 .”
BackgroundWang, N., & Wang, T. (2024) · Biotechnology Journal · doi:10.1002/biot.202300658 · Cited by 11
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“While the LNPs administered were either not previously assessed for widespread tissue delivery 16 or reported to target the liver/lungs, 21–23 robust EGFP splice-switchingwasonlyobservedintheliver.”
BackgroundKimura, S., & Harashima, H. (2024) · BioDrugs · doi:10.1007/s40259-024-00647-4 · Cited by 8
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“The p Ka of LNP was determined using the TNS binding assay 14 . mRNA binding affinity LQ-3 and SM-102 was dissolved in ethanol at a concentration of 6.25 mM respectively.”
BackgroundMethodInfluentialBiocompatible lipid nanovehicles for preventive and therapeutic vaccine development
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Design and Evaluation of Biodegradable Self‐Immolative Lipids for RNA Delivery
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The Overlooked Stereoisomers of the Ionizable Lipid ALC315
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Metadata
- Authors
- Sabnis, S., Kumarasinghe, E. S., Salerno, T., Mihai, C., Ketova, T., Senn, J. J., Lynn, A., Bulychev, A., McFadyen, I., Chan, J., Almarsson, Ö., Stanton, M. G., & Benenato, K. E.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Corresponding author
- Benenato, Kerry E.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 26
- Issue
- 6
- Pages
- 1509-1519
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5986714
- OpenAlex
- W2791854174
- Cited by
- 820
- References
- 20
- Citations by year
- 2026: 107 · 2025: 139 · 2024: 156 · 2023: 139 · 2022: 116 · 2021: 73 · 2020: 51 · 2019: 31 · 2018: 7
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- mRNA delivery, lipid nanoparticles, endosomal escape, structure-activity relationship, pharmacokinetics, toxicology, non-human primates
- MeSH terms
- Animals, Lipids, Primates, RNA, Messenger, Rats, Nanoparticles
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