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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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“It was shown that SM-102 in Moderna’s mRNA vaccine outperformed MC3 [106, 107].”
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Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment
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“In contrast, the limited half-life of LNPformulated mRNA used here (25) leads to controlled and transient protein production, as demonstrated in multiple syngeneic and PDX models.”
BackgroundEndosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale
Paramasivam, P., Franke, C., Stöter, M., Höijer, A., Bartesaghi, S., Sabirsh, A., Lindfors, L., Arteta, M. Y., Dahlén, A., Bak, A., et al. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202110137 · Cited by 238
“Therefore, we performed a systematic comparison of six mRNA-containing LNPs with different cationic lipids, including MOD5, an analogue of the SM-102 lipid used in the Moderna “mRNA-1273” SARS-CoV-2 vaccine (Sabnis et al., 2018), in primary human adipocytes, fibroblasts, and HeLa cells to identify candidate parameters…”
BackgroundMethodIonizable lipid nanoparticles for in utero mRNA delivery
Riley, R. S., Kashyap, M. V., Billingsley, M. M., White, B., Alameh, M.-G., Bose, S. K., Zoltick, P. W., Li, H., Zhang, R., Cheng, A. Y., et al. (2021) · Science Advances · doi:10.1126/sciadv.aba1028 · Cited by 222
Jeong, M., Lee, Y., Park, J., Jung, H., & Lee, H. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114990 · Cited by 232
Functional siRNA Delivery by Extracellular Vesicle–Liposome Hybrid Nanoparticles
Evers, M. J. W., van de Wakker, S. I., de Groot, E. M., de Jong, O. G., Gitz-Francois, J. J., Seinen, C. W., Sluijter, J. P. G., Schiffelers, R. M., & Vader, P. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202101202 · Cited by 229
mRNA Delivery for Therapeutic Anti-HER2 Antibody Expression In Vivo
Rybakova, Y., Kowalski, P. S., Huang, Y., Gonzalez, J. T., Heartlein, M. W., DeRosa, F., Delcassian, D., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.05.012 · Cited by 218
Formulation and Delivery Technologies for mRNA Vaccines
Zeng, C., Zhang, C., Walker, P. G., & Dong, Y. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_217 · Cited by 228
Pharmacokinetic and Pharmacodynamic Properties of Drug Delivery Systems
Glassman, P. M., & Muzykantov, V. R. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.119.257113 · Cited by 222
“, 2009) or lipids (Du et al., 2014; Sabnis et al., 2018) into the nanoparticle to facilitate cytoplasmic release; or 3) reliance on natural”
Non-viral COVID-19 vaccine delivery systems
Park, K. S., Sun, X., Aikins, M. E., & Moon, J. J. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.008 · Cited by 216
“based on rational design; C12-200 [28] and cKK-E12 [29], which were identified by high throughout screenings of large combinatorial libraries; L319 [30], TT3 [31], ssPalmE [32], Acuitas (A9) [33] and Moderna (L5) [34], which are biodegradable.”
RNA interference in the era of nucleic acid therapeutics
Jadhav, V., Vaishnaw, A. K., Fitzgerald, K. J., & Maier, M. A. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-02105-y · Cited by 232
Artificial intelligence-driven rational design of ionizable lipids for mRNA delivery
Wang, W., Chen, K., Jiang, T. S., Wu, Y., Wu, Z., Ying, H., Yu, H., Lu, J., Lin, J., & Ouyang, D. (2024) · Nature Communications · doi:10.1038/s41467-024-55072-6 · Cited by 247
“Previous studies have established the signi fi cance of the apparent pKa of LNPs 8,12,18 .”
InfluentialKose, N., Fox, J. M., Sapparapu, G., Bombardi, R., Tennekoon, R. N., de Silva, A. D., Elbashir, S. M., Theisen, M. A., Humphris-Narayanan, E., Ciaramella, G., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aaw6647 · Cited by 202
Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis
Han, X., Gong, N., Xue, L., Billingsley, M. M., El-Mayta, R. D., Shepherd, S. J., Alameh, M., Weissman, D., & Mitchell, M. J. (2023) · Nature Communications · doi:10.1038/s41467-022-35637-z · Cited by 206
Wahane, A. V., Waghmode, A., Kapphahn, A., Dhuri, K., Gupta, A., & Bahal, R. (2020) · Molecules · doi:10.3390/molecules25122866 · Cited by 202
“Lipid 5-based LNPs also demonstrated superior pharmacokinetic profile with decreased liver accumulation at clinically relevant doses (1–2 mg/kg dose per week over 5 weeks) in both rats and cynomolgus monkeys [37].”
BackgroundA microneedle vaccine printer for thermostable COVID-19 mRNA vaccines
Straeten, A. V., Sarmadi, M., Daristotle, J. L., Kanelli, M., Tostanoski, L. H., Collins, J., Pardeshi, A., Han, J., Varshney, D., Eshaghi, B., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-023-01774-z · Cited by 199
Combinatorial development of nebulized mRNA delivery formulations for the lungs
Jiang, A. Y., Witten, J. J., Raji, I. O., Eweje, F., MacIsaac, C., Meng, S., Oladimeji, F. A., Hu, Y., Manan, R. S., Langer, R., et al. (2023) · Nature Nanotechnology · doi:10.1038/s41565-023-01548-3 · Cited by 215
Bost, J., Barriga, H. M. G., Holme, M. N., Gallud, A., Maugeri, M., Gupta, D., Lehto, T., Valadi, H., Esbjörner, E. K., Stevens, M. M., et al. (2021) · ACS Nano · doi:10.1021/acsnano.1c05099 · Cited by 189
Extracellular vesicles induce minimal hepatotoxicity and immunogenicity
Saleh, A. F. A., Lázaro‐Ibáñez, E., Forsgard, M., Shatnyeva, O., Osteikoetxea, X., Karlsson, F. H., Heath, N., Ingelsten, M., Rose, J., Harris, J., et al. (2019) · Nanoscale · doi:10.1039/c8nr08720b · Cited by 186
Recent Advances in the Lipid Nanoparticle-Mediated Delivery of mRNA Vaccines
Swetha, K., Kotla, N. G., Tunki, L., Jayaraj, A., Bhargava, S. K., Hu, H., Bonam, S. R., & Kurapati, R. (2023) · Vaccines · doi:10.3390/vaccines11030658 · Cited by 196
“FTT5 is a well-studied ionizable lipid wit nhanced mRNA delivery for protein supplementing applications [36,43].”
BackgroundInfluentialSystemic messenger RNA as an etiological treatment for acute intermittent porphyria
Jiang, L., Berraondo, P., Jericó, D., Guey, L. T., Sampedro, A., Frassetto, A., Benenato, K. E., Burke, K., Santamaría, E., Alegre, M., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0199-z · Cited by 181
Self-citationSmart Biomaterials: Recent Advances and Future Directions
Kowalski, P. S., Bhattacharya, C., Afewerki, S., & Langer, R. (2018) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b00889 · Cited by 189
Recent Advances in Lipid Nanoparticles for Delivery of mRNA
Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F. H., Zhang, Z., Li, Y., & Huang, W. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14122682 · Cited by 190
Nanotechnology-based mRNA vaccines
Chen, S., Huang, X., Xue, Y., Álvarez‐Benedicto, E., Shi, Y., Chen, W., Koo, S., Siegwart, D. J., Dong, Y., & Tao, W. (2023) · Nature Reviews Methods Primers · doi:10.1038/s43586-023-00246-7 · Cited by 177
Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery
Herrera‐Barrera, M., Kim, J., Eygeris, Y., Jozić, A., & Sahay, G. (2021) · Biomaterials Science · doi:10.1039/d0bm01947j · Cited by 180
Rui, Y., Wilson, D. R., Tzeng, S. Y., Yamagata, H. M., Sudhakar, D., Conge, M., Berlinicke, C. A., Zack, D. J., Tuesca, A. D., & Green, J. J. (2022) · Science Advances · doi:10.1126/sciadv.abk2855 · Cited by 171
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“were prepared by ethanol-drop nanoprecipitation as previously described.(30) Briefly, lipids dissolved in ethanol at a molar ratio of 50:10:38.”
MethodSelf-citationDeveloping Biodegradable Lipid Nanoparticles for Intracellular mRNA Delivery and Genome Editing
Qiu, M., Li, Y., Bloomer, H., & Xu, Q. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00500 · Cited by 168
Prediction of lipid nanoparticles for mRNA vaccines by the machine learning algorithm
Wang, W., Feng, S., Ye, Z., Gao, H., Lin, J., & Ouyang, D. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.11.021 · Cited by 173
“DSPC, the helper lipid, is related to LNP structure 22,23 , interfacial tension 24 , and helps mRNA release 25 .”
BackgroundSzebeni, J., Storm, G., Ljubimova, J. Y., Castells, M., Phillips, E. J., Turjeman, K., Barenholz, Y., Crommelin, D. J. A., & Dobrovolskaia, M. A. (2022) · Nature Nanotechnology · doi:10.1038/s41565-022-01071-x · Cited by 170
mRNA cancer vaccines: Advances, trends and challenges
He, Q., Gao, H., Tan, D., Zhang, H., & Wang, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.011 · Cited by 171
“…bacterial pathogens 20 ( Mycobacterium tuberculosis 21 ) and cancer 22,23 ] and as a protein replacement platform ( e . g ., factor IX 24 , follistatin 25 , ornithine transcarbamylase 26 and erythropoietin 27 ) for prevention and treatment of disease. mRNA vaccines have many shared characteristics.”
Li, B., Jiang, A. Y., Raji, I. O., Atyeo, C. G., Raimondo, T. M., Gordon, A. G. R., Rhym, L. H., Samad, T. S., MacIsaac, C., Witten, J. J., et al. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01082-6 · Cited by 176
“Recent data suggest that the early development of FcR-binding antibodies can potentially predict the resolution of severe COVID-19 49,50 .”
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“Three major hurdles must be addressed: rapid degradation and lack of localization of naked RNA; impeded passive uptake due to the RNA’s large, polyanionic nature (4); and the necessity for safe, well - tolerated, and body - clearable delivery vehicles (5, 6).”
Zhang, D., Atochina‐Vasserman, E. N., Maurya, D. S., Huang, N., Xiao, Q., Ona, N. A., Liu, M., Shahnawaz, H., Ni, H., Kim, K., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c05813 · Cited by 164
Research Advances on the Stability of mRNA Vaccines
Cheng, F., Wang, Y., Bai, Y., Liang, Z., Mao, Q., Liu, D., Wu, X., & Xu, M. (2023) · Viruses · doi:10.3390/v15030668 · Cited by 177
“mRNAs can be protected by LNPs from ribonuclease degradation and enter cells by endocytosis then escape into the cytoplasm via endosomes to complete mRNA translation and expression [76].”
BackgroundArtificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy
Witten, J. J., Raji, I. O., Manan, R. S., Beyer, E., Bartlett, S., Tang, Y., Ebadi, M., Lei, J., Nguyen, D., Oladimeji, F. A., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02490-y · Cited by 197
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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