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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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“However, different types and numerous doses of vaccines are still needed to meet the global demand and to cope with new emerging variants (Sabnis et al., 2018; Tegally et al., 2021; Zhang et al., 2021).”
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“Ionizable lipids are neutral at physiological pH, but at acidic pH B 5, they become positively charged, and when mixed with negatively charged RNA, mRNA-LNPs are formed (Sabnis et al .”
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Ferraresso, F., Badior, K. E., Seadler, M. S., Zhang, Y., Wietrzny, A., Cau, M. F., Haugen, A., Rodriguez, G. G., Dyer, M., Cullis, P. R., et al. (2024) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2024.101314 · Cited by 20
Arshad, M., Atochina‐Vasserman, E. N., Chenna, S. S., Maurya, D. S., Shalihin, M. I., Sahoo, D., Lewis, A. C., Lewis, J. J., Ona, N. A., Vasserman, J. A., et al. (2024) · Biomacromolecules · doi:10.1021/acs.biomac.4c01107 · Cited by 15
Yoshinaga, N., Naito, M., Tachihara, Y., Boonstra, E., Osada, K., Cabral, H., & Uchida, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13060800 · Cited by 16
“Cationic materials can also be designed to modulate the intracellular processes, for example, by facilitating endosomal escape [10] and preventing intracellular mRNA degradation [11].”
BackgroundEdwards, D. K., & Carfı́, A. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102214 · Cited by 18
Structure–Activity Relationship of Ionizable Lipids for siRNA and mRNA Lipid Nanoparticle Design
Lee, S. M., Sun, Y., Chatterjee, S., Xiong, H., Cheng, Q., Wang, X., & Siegwart, D. J. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c00463 · Cited by 14
Meerasa, S. S., Ahmad, A., Khan, A. A., Haque, S., & Saleem, I. Y. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.126263 · Cited by 14
Degradable cyclic amino alcohol ionizable lipids as vectors for potent influenza mRNA vaccines
Rudra, A., Gupta, A., Reed, K., Deik, A., Min, J., Mansour, H. M. A., Nguyen, Q. T. C., Danko, A., Hu, Y., Berger, A., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-025-02044-6 · Cited by 18
“We believe that these insights into the relationship between LNP chemistry and RNA delivery may assist in the generation of next-generation ionizable lipids for delivery 13,66–68 .”
InfluentialQiu, X., Yang, Y., Ma, Q., Zheng, B., Chen, Z., Wu, F., Zhou, B., & Xiong, H. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c19387 · Cited by 14
Lipid-Based Colloidal Nanocarriers for Site-Specific Drug Delivery
Shameli, K., Kalali, B. N., Moeini, H., & Kartouzian, A. (2026) · Colloids and Interfaces · doi:10.3390/colloids10010007 · Cited by 14
“FTT5 effectively delivers large mRNAs for protein supplementation and base-editing therapies, highlighting tail branching as a key design feature in LNP development [68].”
Zhao, Y., Liu, C., Zhang, X., Gu, T., Wang, Y., Zuo, T., Liu, S., Xu, X., & Meng, H. (2026) · ACS Nano · doi:10.1021/acsnano.5c21857 · Cited by 18
Nie, X., Liu, Y., Song, Y., Yao, X., Chen, Y., Lee, H., & Gao, X. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.ady6730 · Cited by 17
Wang, J., Zhang, Y., Dong, S., Zha, W., Liu, C., Wang, Y., Jiang, Y., Xing, H., & Li, X. (2023) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2023.123155 · Cited by 15
Recent Advances in Messenger Ribonucleic Acid (mRNA) Vaccines and Their Delivery Systems: A Review
Belay, W. Y., Nibret, G., & Aschale, Y. (2023) · Clinical Pharmacology Advances and Applications · doi:10.2147/cpaa.s418314 · Cited by 16
“5% of mRNA was detected in the cytosol after transfection of human epithelial cells with mRNA, and this varies by cell type.(129,184,284,285) Additionally, the methods utilized to avoid this terminal degradation rely on units that are activated by acidic pH.”
MethodAdvances in the development of lipid nanoparticles for ophthalmic therapeutics
Chen, S., Deng, Z., & Ji, D. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117108 · Cited by 16
López-Pascual, A., Russo-Cabrera, J. S., Ardaiz, N., Palmer, T., Graham, A.-R., Uriarte, I., Gomar, C., Ruiz-Guillamon, D., Latasa, M. U., Arechederra, M., et al. (2024) · Clinical Science · doi:10.1042/cs20241137 · Cited by 14
Börjesdotter, A.-M., Bolinsson, H., Dagø, T., Herranz-Trillo, F., Palmiero, U. C., Schagerlöf, H., & Nilsson, L. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124940 · Cited by 15
Koyra, N., Yu, H., Drummond, C. J., Zhai, J., & Dyett, B. (2025) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2025.2518225 · Cited by 15
Delnoy, B., Haskovic, M., Vanoevelen, J. M., Steinbusch, L. K. M., Vos, E. N., Knoops, K., Zimmermann, L. J. I., Noga, M. J., Lefeber, D. J., Martini, P. G. V., et al. (2022) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12512 · Cited by 14
“Expression of a luciferase reporter mRNA delivered by an LNP was predominantly expressed in the liver.(35) Moreover, expression of an Epo reporter mRNA delivered by an LNP is greatly diminished in LDL receptor deficient mice.”
BackgroundParra-Guillen, Z. P., Fontanellas, A., Jiang, L., Jericó, D., Martini, P. G. V., Vera‐Yunca, D., Hard, M., Guey, L. T., & Trocóniz, I. F. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15040 · Cited by 14
“Once invaginated, LNPs are optimized to provide high delivery rates and better endosomal escape once invaginated (Sabnis et al., 2018).”
BackgroundApplying machine learning to identify ionizable lipids for nanoparticle-mediated delivery of mRNAPreprint
Lewis, M. M., Beck, T. J., & Ghosh, D. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.09.565872 · Cited by 14
“This is especially beneficial for studying ionizable lipids similar to SM-102 and ALC-0315 - while these lipids are among the first ionizable lipids to be used in chemically approved formulations, only a handful of chemical analogs have been reported due to their multi-step synthesis process 15,17 .”
BackgroundCouture‐Senécal, J., Tilstra, G., & Khan, O. F. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.02.606386 · Cited by 16
“25,26 However, the biodegradation kinetics of ester groups can vary drastically based on their susceptibility to enzymatic hydrolysis.”
BackgroundTargeted Drug Delivery to the Spleen and Its Implications for the Prevention and Treatment of Cancer
Khalil, I. A., Faheem, A., & El‐Tanani, M. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17050651 · Cited by 15
“The interaction of NPs with serum apolipoprotein E (ApoE) appears to enhance liver uptake, as DOPE-containing NPs tend to bind more strongly to ApoE, facilitating their delivery to hepatic cells [68,69].”
Li, H. M., Song, P., Li, Y., Tu, S., Mehmood, M., Chen, L., Li, N., & Tian, Q. (2025) · Membranes · doi:10.3390/membranes15050153 · Cited by 16
“The functional efficacy of LNPs primarily depends on the synergistic effects of their structural components [18,19].”
Advances in the rational design of ionizable lipids for mRNA therapeutics
Lee, Y., Guo, K., Oh, M., Kim, E., Jeong, Y., Yoon, Y., Choi, Y., Hwang, Y., Byeon, Y., Dong, Y., et al. (2025) · Materials Today · doi:10.1016/j.mattod.2025.07.028 · Cited by 19
He, Y., Pilkington, E. H., Kang, H. J., Fong, W., Clulow, A. J., Johnston, A. P. R., & Pouton, C. W. (2025) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2025.101578 · Cited by 12
“36 The study by Jayaraman et al. 17 identified that MC3, later used in Onpattro, was one of the most effective of 50 lipids tested in vivo .”
Huang, Y., Liu, S., Zhang, X., Zhang, B., Shi, F., Zhang, J., Shao, S., Han, H., Ma, X., Xie, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66087-y · Cited by 17
“To evaluate the ef fi ciency of its hepatic delivery in vivo, MLX0473-based LNP encapsulating luciferase (Luc) mRNA was injected intravenously into C57BL/6J mice to evaluate bioluminescence distribution versus Lipid5, a widely used ionizable amino lipid for liver-targeted mRNA delivery 29 .”
Immune-Modulating Lipid Nanomaterials for the Delivery of Biopharmaceuticals
Kim, S., Choi, B., Kim, Y., & Shim, G. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15061760 · Cited by 13
“Because LNPs can activate the immune system and cause anaphylactic-like shock, the risk of an acute immune response must be recognized, and solutions must be prepared [54].”
BackgroundShort Carbon Nanotube-Based Delivery of mRNA for HIV-1 Vaccines
Xu, Y., Ferguson, T., Masuda, K., Siddiqui, M. A., Smith, K. P., Vest, O., Brooks, B., Zhou, Z., Obliosca, J. M., Kong, X., et al. (2023) · Biomolecules · doi:10.3390/biom13071088 · Cited by 13
“In the efficacy studies, Luna Labs produced lipid nanoparticles (LNP (MC3)) as a benchmark delivery vehicle to compare with the NanoVac delivery platform, using a published method[18].”
MethodComputational approaches to lipid-based nucleic acid delivery systems
Settanni, G. (2023) · The European Physical Journal E · doi:10.1140/epje/s10189-023-00385-5 · Cited by 14
“[50]simulatedatatomisticres-olutionlipidformulationscontainingtheILLipid5 (heptadecan-9-yl 8-[(2-hydroxyethyl)[8-(nonyloxy)-8- oxooctyl]amino]octanoate),whichresultedasapromis- ingcandidatefromapreviousexperimentalscreen-ing[51].”
Wang, S., Guo, B., Wang, H., & Yang, F. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.105547 · Cited by 14
Rajlic, I. L., Guglieri-López, B., Rangoonwala, N., Ivaturi, V. D., Van, L. M., Mori, S., Wipke, B. T., Burdette, D. S., & Attarwala, H. Z. (2024) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.13142 · Cited by 13
“38,39 mRNA-6231 is an investigational mRNA-based IL-2 therapeutic composed of LNPs encapsulating mRNA that encodes human IL-2 mutein (HSA-IL2m mRNA) fused to human serum albumin (HSA-IL2m).”
Method
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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