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Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey
Abstract
The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested. 24 hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ–inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.
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“In vivo application of lipid nanoparticles has been reported to induce liver and lung injuries in rodents170,173, which may be attributed to the cytotoxicity of the materials and the induction of”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
In the citing paper
“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
In the citing paper
“Cationic and ionizable lipids have also been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species170–173.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
Citations
Cites
Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005) · Immunity · doi:10.1016/j.immuni.2005.06.008 · Cited by 2,728
mRNA-based therapeutics--developing a new class of drugs
Sahin, U., Karikó, K., & Türeci, Ö. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4278 · Cited by 2,474
Protein Therapeutics: A Summary and Pharmacological Classification
Leader, B., Baca, Q. J., & Golan, D. E. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2399 · Cited by 2,161
Rational design of cationic lipids for siRNA delivery
Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W. Y., Stebbing, D., Crosley, E. J., Yaworski, E., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1602 · Cited by 1,822 · cited 1×
“However, the application of lipid-based nanoparticle delivery systems, initially developed for the in vivo delivery of siRNA, has enabled systemic administration of modified mRNA.(22)”
BackgroundGilleron, J., Querbes, W., Zeigerer, A., Borodovsky, A., Marsico, G., Schubert, U., Manygoats, K., Seifert, S., Andree, C., Stöter, M., et al. (2013) · Nature Biotechnology · doi:10.1038/nbt.2612 · Cited by 1,681
RNAi-mediated gene silencing in non-human primates
Zimmermann, T. S., Lee, A. C. H., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., et al. (2006) · Nature · doi:10.1038/nature04688 · Cited by 1,357 · cited 1×
“The mRNA-loaded LNPs were generated via stepwise ethanol dilution, with an approach adapted from previously demonstrated methods.(13,30) The LNP formulation was prepared by dissolving the lipids (6Z,9Z,28Z,31Z)-heptatriaconta6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 2 Veterinary Pathology XX(X)”
MethodShatkin, A. J. (1976) · Cell · doi:10.1016/0092-8674(76)90128-8 · Cited by 1,180
Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B. L., Tam, Y. K., Madden, T. D., Hope, M. J., & Weissman, D. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.007 · Cited by 1,014
Safety and efficacy of RNAi therapy for transthyretin amyloidosis
Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1208760 · Cited by 971
Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
Kormann, M. S. D., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., et al. (2011) · Nature Biotechnology · doi:10.1038/nbt.1733 · Cited by 733
Research works printed but not linked: 1
- Casadevall N, 2003, Nephrol Dial Transplant, 18, viii37
Cited by
Sorted by citations
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Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076
Drug delivery systems for RNA therapeutics
Paunovska, K., Loughrey, D., & Dahlman, J. E. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00439-4 · Cited by 1,349
Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery
Kowalski, P. S., Rudra, A., Miao, L., & Anderson, D. G. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.012 · Cited by 1,127
“Inspired by the success of LNPs, various groups showed that MC3 can also be used to safely transfect mRNA in order to express therapeutic proteins.(32,33) Researchers at Intellia Therapeutics have reported an ionizable lipid named LP-01 (Figure 2) as part of”
Sabnis, S., Kumarasinghe, E. S., Salerno, T., Mihai, C., Ketova, T., Senn, J. J., Lynn, A., Bulychev, A., McFadyen, I., Chan, J., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.03.010 · Cited by 820
Self-citationCRISPR/Cas9 therapeutics: progress and prospects
Li, T., Yang, Y., Qi, H., Cui, W., Zhang, L., Fu, X., He, X., Liu, M., Li, P., & Yu, T. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01309-7 · Cited by 824
“A gold standard MC-3 LNP configured with cholesterol, DSPC and DMG-PEG was used as a control to screen for the most efficient 306-O12B LNP consisting of a leading tail-branched bioreducible lipidoid (306-O12B) and an optimized mixture of excipient lipid molecules.(197) The gene-editing efficiency of this LNP reached 3…”
MethodAdvances in mRNA Vaccines for Infectious Diseases
Zhang, C., Maruggi, G., Shan, H., & Li, J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00594 · Cited by 696
Ndeupen, S., Qin, Z., Jacobsen, S., Bouteau, A., Estanbouli, H., & Igyártó, B. Z. (2021) · iScience · doi:10.1016/j.isci.2021.103479 · Cited by 678
“The cationic lipid component of the lipid carriers is often inflammatory and cytotoxic (Filion and Phillips, 1997, 1998; Lv et al., 2006; Samaridou et al., 2020; Sedic et al., 2018; Tao et al., 2011).”
Opportunities and Challenges in the Delivery of mRNA-Based Vaccines
Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C., & Thakur, A. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12020102 · Cited by 584
Lipid nanoparticles for nucleic acid delivery: Current perspectives
Samaridou, E., Heyes, J. A., & Lutwyche, P. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.002 · Cited by 609
Nanomaterial Delivery Systems for mRNA Vaccines
Buschmann, M. D., Carrasco, M. J., Alishetty, S., Paige, M., Alameh, M. G., & Weissman, D. (2021) · Vaccines · doi:10.3390/vaccines9010065 · Cited by 582
“3 mg/kg, which is more than 10-fold the expected therapeutic dose [167].”
BackgroundAddressing the Cold Reality of mRNA Vaccine Stability
Crommelin, D. J. A., Anchordoquy, T. J., Volkin, D. B., Jiskoot, W., & Mastrobattista, E. (2021) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2020.12.006 · Cited by 517
Kim, J., Eygeris, Y., Gupta, M., & Sahay, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.014 · Cited by 514
The landscape of mRNA nanomedicine
Huang, X., Kong, N., Zhang, X., Cao, Y., Langer, R., & Tao, W. (2022) · Nature Medicine · doi:10.1038/s41591-022-02061-1 · Cited by 511
A Comprehensive Review of mRNA Vaccines
Gote, V., Bolla, P. K., Kommineni, N., Butreddy, A., Nukala, P. K., Palakurthi, S. S., & Khan, W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032700 · Cited by 457
Parayath, N. N., Stephan, S. B., Koehne, A. L., Nelson, P. S., & Stephan, M. T. (2020) · Nature Communications · doi:10.1038/s41467-020-19486-2 · Cited by 457
Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Maugeri, M., Nawaz, M., Papadimitriou, A., Angerfors, A., Camponeschi, A., Na, M., Hölttä, M., Skantze, P., Johansson, S., Sundqvist, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12275-6 · Cited by 428
The challenge and prospect of mRNA therapeutics landscape
Weng, Y., Li, C., Yang, T., Hu, B., Zhang, M., Guo, S., Xiao, H., Liang, X.-J., & Huang, Y. (2020) · Biotechnology Advances · doi:10.1016/j.biotechadv.2020.107534 · Cited by 417
Qiu, M., Glass, Z., Chen, J., Haas, M., Jin, X., Zhao, X., Rui, X., Ye, Z., Li, Y., Zhang, F., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020401118 · Cited by 423
“This excipient ratio has been reported in the literature to be effective (29).”
BackgroundMethodmRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection
Xu, S., Yang, K., Li, R., & Zhang, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186582 · Cited by 368
In vivo CAR T cell generation to treat cancer and autoimmune disease
Hunter, T., Bao, Y., Zhang, Y., Matsuda, D., Riener, R. M., Wang, A., Li, J., Soldevila, F., Chu, D. S. H., Nguyen, D. H. V., et al. (2025) · Science · doi:10.1126/science.ads8473 · Cited by 370
Lipid-Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Components
Kazemian, P., Yu, S.-Y., Thomson, S. B., Birkenshaw, A., Leavitt, B. R., & Ross, C. J. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00916 · Cited by 358
AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery
Xu, Y., Ma, S., Cui, H., Chen, J., Xu, S., Gong, F., Golubovic, A., Zhou, M., Wang, K. C., Varley, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50619-z · Cited by 272
Strategies to reduce the risks of mRNA drug and vaccine toxicity
Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00859-3 · Cited by 242
“Rat and non-human primates are also used in mRNA safety and tolerability studies. mRNA encoding hEPO was formulated in LNPs and administered intravenously in both species 100 .”
Self-citationNanomedicines to Deliver mRNA: State of the Art and Future Perspectives
Gómez-Aguado, I., Rodríguez-Castejón, J., Vicente-Pascual, M., Rodríguez‐Gascón, A., Solinís, M. Á., & del Pozo‐Rodríguez, A. (2020) · Nanomaterials · doi:10.3390/nano10020364 · Cited by 229
Ionizable 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
“However, it is important to note that other ionizable LNPs have been evaluated for safety in adult mice, in nonhuman primates, and in clinical trials in humans, which have demonstrated low toxicity overall ( 70 – 72 ).”
BackgroundFormulation 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 227
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
Systemic 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
Aldén, M., Falla, F. O., Yang, D., Barghouth, M., Luan, C., Rasmussen, M., & Marinis, Y. Z. D. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44030073 · Cited by 184
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
Nanoscale platforms for messenger RNA delivery
Li, B., Zhang, X., & Dong, Y. (2019) · WIREs Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1530 · Cited by 170
“In 2017, Sedic et al. (2017) reported a safety evaluation of lipid nanoparticles loaded with human erythropoietin (hEPO) mRNA in both Sprague-Dawley rats and cynomolgus monkeys, which established its pharmacology, pharmacokinetics, and safety profile.”
BackgroundInfluentialmRNA 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 169
“Intravenous administration allows for a larger vaccine volume and direct delivery of the vaccine into the lymphatic organs 168 but also carries a greater risk of systemic toxicity 169,170 .”
Szebeni, 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
Chen, J., Xu, Y., Zhou, M., Xu, S., Varley, A., Golubovic, A., Lu, R. X. Z., Wang, K. C., Yeganeh, M., Vosoughi, D., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309472120 · Cited by 169
“Rodent studies have shown that LNPs containing nonbiodegradable ionizable lipids can cause liver damage (22–24), underlining the imperative for biodegradable lipid design.”
Aerosolizable Lipid Nanoparticles for Pulmonary Delivery of mRNA through Design of Experiments
Zhang, H., Leal, J., Soto, M. R., Smyth, H. D. C., & Ghosh, D. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12111042 · Cited by 163
Current Status and Future Perspectives on MRNA Drug Manufacturing
Webb, C., Ip, S. Y., Bathula, N. V., Popova, P. G., Soriano, S. K. V., Ly, B.-H., Eryilmaz, B., Huu, V. A. N., Broadhead, R., Rabel, M., et al. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.2c00010 · Cited by 134
The NIH Somatic Cell Genome Editing program
Saha, K., Sontheimer, E. J., Brooks, P. J., Dwinell, M. R., Gersbach, C. A., Liu, D. R., Murray, S. A., Tsai, S. Q., Wilson, R. C., Anderson, D. G., et al. (2021) · Nature · doi:10.1038/s41586-021-03191-1 · Cited by 127
Development and Delivery Systems of mRNA Vaccines
Liang, Y., Huang, L., & Liu, T. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.718753 · Cited by 125
“Maja et al. (2018) evaluated the safety of LNP packaging of human erythropoietin (hEPO) mRNA in monkeys and rats. following intravenous injection of 0.3 mg/kg mRNA LNP, hEPO levels were highest at 6 h post-infusion and exceeded the expected effective exposure 100-fold at the maximal dose.”
BackgroundInfluentialEmerging vaccine nanotechnology: From defense against infection to sniping cancer
Feng, C., Li, Y., Ferdows, B. E., Patel, D. N., Ouyang, J., Tang, Z., Kong, N., Chen, E., & Tao, W. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.12.021 · Cited by 131
Quality by Design for enabling RNA platform production processes
Daniel, S., Kis, Z., Kontoravdi, C., & Shah, N. (2022) · Trends in biotechnology · doi:10.1016/j.tibtech.2022.03.012 · Cited by 129
mRNA therapeutics deliver a hopeful message
Zhong, Z., Cafferty, S. M., Combes, F., Huysmans, H., Temmerman, J. D., Gitsels, A., Vanrompay, D. C. G., Catani, J. P., & Sanders, N. N. (2018) · Nano Today · doi:10.1016/j.nantod.2018.10.005 · Cited by 124
Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms
Michels, A., Ho, N., & Buchholz, C. J. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.05.018 · Cited by 129
Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases
Trepotec, Z., Lichtenegger, E., Plank, C., Aneja, M. K., & Rudolph, C. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.12.012 · Cited by 115
mRNA vaccines for COVID-19 and diverse diseases
Hussain, A., Yang, H., Zhang, M., Liu, Q., Alotaibi, G., Irfan, M. F., He, H., Chang, J. K., Liang, X., Weng, Y., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.032 · Cited by 121
“Human erythropoietin N/A MC3, DSPC, cholesterol, and PEG2000-DMG [197]”
Lam, K., Leung, A., Martin, A., Wood, M., Schreiner, P., Palmer, L., Daly, O. M., Zhao, W., McClintock, K., & Heyes, J. A. (2023) · Advanced Materials · doi:10.1002/adma.202209624 · Cited by 118
Non-immunotherapy application of LNP-mRNA: Maximizing efficacy and safety
Vlatkovic, I. (2021) · Biomedicines · doi:10.3390/biomedicines9050530 · Cited by 112
Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors
Anthiya, S., Öztürk, S. C., Yanık, H., Tavukçuoğlu, E., Şahin, A., Datta, D., Charissé, K., Moreira, D., Loza, M. I., Calvo, A., et al. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.03.016 · Cited by 102
Lipid Nanoparticles for Delivery of Therapeutic RNA Oligonucleotides
Moss, K. H., Popova, P. G., Hadrup, S. R., Astakhova, K., & Taskova, M. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.8b01290 · Cited by 101
Poly(carboxybetaine) lipids enhance mRNA therapeutics efficacy and reduce their immunogenicity
Luozhong, S., Liu, P., Li, R., Yuan, Z., Debley, E. L., Chen, Y., Hu, Y., Cao, Z., Cui, M., McIlhenny, K., et al. (2025) · Nature Materials · doi:10.1038/s41563-025-02240-8 · Cited by 106
“First, we evaluated the liver toxicity of the PEG-LNPs and PCB-LNPs by measuring two clinical chemistry markers, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 22,38,39 .”
Synthetic modified messenger RNA for therapeutic applications
Gao, M., Zhang, Q., Feng, X.-H., & Liu, J. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.06.020 · Cited by 89
Bouazzaoui, A., Abdellatif, A. A. H., Al-Allaf, F. A., Bogari, N. M., Al-Dehlawi, S., & Qari, S. H. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020140 · Cited by 92
Frameworks for transformational breakthroughs in RNA-based medicines
Androsavich, J. R. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-00943-2 · Cited by 96
“100), consistent with other reports of systemic elevation of pro-inflammatory cytokine and innate immune responses induced by RNA-nanoparticle treatment 120,128,136 .”
Davies, N. M., Hovdal, D., Edmunds, N. J., Nordberg, P., Dahlén, A., Dabkowska, A. P., Arteta, M. Y., Rădulescu, A., Kjellman, T., Höijer, A., et al. (2021) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2021.03.008 · Cited by 90
Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles
Brown, D. W., Wee, P., Bhandari, P., Bukhari, A. B., Grin, L., Vega, H., Hejazi, M., Sosnowski, D. L., Ablack, J., Clancy, E. K., et al. (2024) · Cell · doi:10.1016/j.cell.2024.07.023 · Cited by 84
Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines
Rinoldi, C., Zargarian, S. S., Nakielski, P., Li, X., Liguori, A., Petronella, F., Presutti, D., Wang, Q., Costantini, M., Sio, L. D., et al. (2021) · Small Methods · doi:10.1002/smtd.202100402 · Cited by 77
Montano, D. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2021.756633 · Cited by 70
Zhang, H., & Barz, M. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.02.055 · Cited by 80
Hashiba, A., Toyooka, M., Sato, Y., Maeki, M., Tokeshi, M., & Harashima, H. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.08.031 · Cited by 66
Samsa, M. M., Dupuy, L. C., Beard, C. W., Six, C. M., Schmaljohn, C. S., Mason, P. W., Geall, A. J., Ulmer, J. B., & Yu, D. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2018.12.013 · Cited by 63
A holistic analysis of the intrinsic and delivery-mediated toxicity of siRNA therapeutics
Ranjbar, S., Zhong, X., Manautou, J. E., & Lü, X. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115052 · Cited by 69
Composition of lipid nanoparticles for targeted delivery: application to mRNA therapeutics
Vasileva, O., Zaborova, O. V., Shmykov, B., Ivanov, R. A., & Reshetnikov, V. V. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1466337 · Cited by 72
Dézsi, L., Mészáros, T., Kozma, G. T., H-Velkei, M., Oláh, C. Z., Szabó, M., Patkó, Z., Fülöp, T., Hennies, M., Szebeni, M., et al. (2022) · GeroScience · doi:10.1007/s11357-021-00495-y · Cited by 58
“The fact that PEGylated, mRNA containing LNPs can activate C is not new; it was described, among others, in human serum in vitro [73] and in rats and monkeys in vivo [74].”
BackgroundYuan, Z., Yan, R., Fu, Z., Wu, T., & Ren, C. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.172240 · Cited by 61
mRNA, a Revolution in Biomedicine
Baptista, B., Carapito, R., Laroui, N., Pichon, C., & de Sousa, F. P. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13122090 · Cited by 61
Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy
Wang, Y., Zhang, R., Tang, L., & Li, Y. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14030512 · Cited by 58
“concluded that the toxicological effects and possibly the distribution properties of the drug product are predominantly vehicle driven [88].”
BackgroundmRNA vaccines contribute to innate and adaptive immunity to enhance immune response in vivo
Cao, Q., Fang, H., & Tian, H. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122628 · Cited by 56
Humphreys, S. C., Davis, J. A., Iqbal, S., Kamel, A. M., Kulmatycki, K. M., Lao, Y., Liu, X., Rodgers, J., Snoeys, J., Vigil, A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac456 · Cited by 49
Lv, K., Yu, Z., Wang, J., Li, N., Wang, A., Xue, T., Wang, Q., Shi, Y., Han, L., Qin, W., et al. (2024) · Advanced Science · doi:10.1002/advs.202404684 · Cited by 53
Advances in the design and delivery of RNA vaccines for infectious diseases
Lokras, A. G., Bobak, T. R., Baghel, S. S., Sebastiani, F., & Foged, C. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115419 · Cited by 52
Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis
Younis, M. A., Sato, Y., Elewa, Y. H. A., Kon, Y., & Harashima, H. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.12.020 · Cited by 48
Potential health risks of mRNA-based vaccine therapy: A hypothesis
Acevedo‐Whitehouse, K. A., & Bruno, R. (2023) · Medical Hypotheses · doi:10.1016/j.mehy.2023.111015 · Cited by 56
“[86] Sedic M, Senn JJ, Lynn A, Laska M, Smith M, Platz SJ, et al.”
BackgroundmRNA delivery in cancer immunotherapy
Zhong, Y., Du, S., & Dong, Y. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.03.001 · Cited by 49
The dynamic process of mRNA delivery by lipid nanoparticles in vivo
Ma, R., Li, Y., Wei, Y., Zhou, J., Ma, J., Zhang, M., Tu, J., Jiang, J., Xie, S., Tan, W., et al. (2024) · Nano Today · doi:10.1016/j.nantod.2024.102325 · Cited by 46
Delivery of synthetic mRNAs for tissue regeneration
Steinle, H., Weber, M., Stoppelkamp, S., Große‐Berkenbusch, K., Golombek, S., Weber, M., Çanak-Ipek, T., Trenz, S.-M., Schlensak, C., & Avci‐Adali, M. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114007 · Cited by 42
Rohde, C. M., Lindemann, C., Giovanelli, M. A., Sellers, R. S., Diekmann, J., Choudhary, S., Ramaiah, L., Vogel, A. B., Chervona, Y., Muik, A., et al. (2023) · Vaccines · doi:10.3390/vaccines11020417 · Cited by 44
“It has been demonstrated that the structure of the ionizable lipid in LNPs has an impact on the local reactogenicity and cytokine expression with parenteral administration [33,62,63].”
BackgroundAre inhaled mRNA vaccines safe and effective? A review of preclinical studies
Jansen, E. M., Frijlink, H. W., Hinrichs, W. L. J., & Ruigrok, M. J. R. (2022) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2022.2131767 · Cited by 37
Welink, J., Xu, Y., Yang, E., Wilson, A., Henderson, N., Luo, L., Fraser, S., Kavita, U., Musuku, A., James, C. A., et al. (2018) · Bioanalysis · doi:10.4155/bio-2018-0268 · Cited by 39
Self-citationOral delivery of nucleic acid therapeutics: Challenges, strategies, and opportunities
Jiang, X., Wang, N., Liu, C., Zhuo, Y., Li, L., Gan, Y., & Yu, M. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103507 · Cited by 38
Delivery of mRNA Vaccine against SARS-CoV-2 Using a Polyglucin:Spermidine Conjugate
Карпенко, Л. И., Рудометов, А. П., Sharabrin, S. V., Щербаков, Д. Н., Borgoyakova, M. B., Bazhan, S. I., Volosnikova, E. A., Борисовна, Р. Н., Orlova, L. A., Pyshnaya, I. A., et al. (2021) · Vaccines · doi:10.3390/vaccines9020076 · Cited by 40
“By adhering to cell surfaces, liposomes can destabilize the cell membrane and cause toxic reactions in vaccinated people [18].”
BackgroundRegulatory Considerations on the Development of mRNA Vaccines
Naik, R., & Peden, K. (2020) · Current topics in microbiology and immunology · doi:10.1007/82_2020_220 · Cited by 37
Yan, J., Zhang, H., Li, G., Su, J., Wei, Y., & Xu, C. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.10.012 · Cited by 40
Silicon Ether Ionizable Lipids Enable Potent mRNA Lipid Nanoparticles with Rapid Tissue Clearance
Holland, R., Lam, K., Jeng, S. C. Y., McClintock, K., Palmer, L., Schreiner, P., Wood, M., Zhao, W., & Heyes, J. A. (2024) · ACS Nano · doi:10.1021/acsnano.3c09028 · Cited by 38
Korzun, T., Moses, A. S., Diba, P., Sattler, A. L., Taratula, O. R., Sahay, G., Taratula, O., & Marks, D. L. (2023) · Pharmaceuticals · doi:10.3390/ph16081088 · Cited by 38
Novel Vectors and Administrations for mRNA Delivery
Bai, C., Wang, C., & Lu, Y. (2023) · Small · doi:10.1002/smll.202303713 · Cited by 32
Cell Membrane‐Coated Lipid Nanoparticles for Drug Delivery
Zewail, M. B., Yang, G., Fan, Y., Hui, Y., Zhao, C., & Liu, Y. (2025) · Aggregate · doi:10.1002/agt2.70054 · Cited by 34
“In some studies, administering LNPs to rodents caused lung and liver injuries due to the activation of various proinflammatory factors [6, 316, 317].”
Elucidating lipid nanoparticle properties and structure through biophysical analyses
Padilla, M. S., Shepherd, S. J., Hanna, A. R., Kurnik, M., Zhang, X., Chen, M., Byrnes, J., Joseph, R. A., Yamagata, H. M., Ricciardi, A. S., et al. (2025) · Nature Biotechnology · doi:10.1038/s41587-025-02855-x · Cited by 38
“Epo is a glycoprotein hormone that stimulates red blood cell production and has been used to assess LNP-induced toxicity 36 .”
mRNA-based modalities for infectious disease management
Zhang, M., Hussain, A., Yang, H., Zhang, J., Liang, X., & Huang, Y. (2022) · Nano Research · doi:10.1007/s12274-022-4627-5 · Cited by 35
Path towards mRNA delivery for cancer immunotherapy from bench to bedside
Chen, W., Zhu, Y., He, J., & Sun, X. (2023) · Theranostics · doi:10.7150/thno.89247 · Cited by 33
“Several mRNA vaccines have undergone extensive testing, ranging from phase I to IIb clinical studies, and have demonstrated a favorable safety profile, being generally safe and well tolerated [152, 153].”
BackgroundNext-generation materials for RNA–lipid nanoparticles: lyophilization and targeted transfection
Wang, T., Sung, T., Yu, T., Lin, H.-Y., Chen, Y.-H., Zhu, Z.-W., Gong, J., Pan, J., & Higuchi, A. (2023) · Journal of Materials Chemistry B · doi:10.1039/d3tb00308f · Cited by 31
Zhang, C., Teng, Y., Bai, X., Tang, M., Stewart, W., Chen, J., Xu, X., & Zhang, X. (2024) · ACS Nano · doi:10.1021/acsnano.4c13404 · Cited by 35
Design principles of lipid nanoparticles for RNA delivery
Arral, M. L., & Whitehead, K. A. (2026) · Nature Reviews Bioengineering · doi:10.1038/s44222-026-00401-1 · Cited by 41
“Following intravenous delivery of erythropoietin mRNA in rats and monkeys, half-lives of 4–7 hours could be measured, using an mRNA assay detection kit 205 .”
Lu, Y., Qian, C., Huang, Y., Ren, T., Xie, W., Xia, N., & Li, S. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.145501 · Cited by 27
Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]
Jawalagatti, V., Kirthika, P., & Lee, J. H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.884862 · Cited by 24
Deng, J., Fukushima, Y., Nozaki, K., Nakanishi, H., Yada, E., Terai, Y., Fueki, K., & Itaka, K. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14091785 · Cited by 24
“Lipid nanoparticles (LNP) are the most commonly used mRNA delivery methods, but the immune–stimulation property of the LNP may interfere with the therapeutic effect of the mRNA, especially for anti-inflammatory therapy [22,23].”
BackgroundDe, A., & Ko, Y. T. (2022) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2023.2153832 · Cited by 24
“Furthermore, ionizable lipids may activate serum complement, resulting in non-IgE-mediated hypersensitivity and anaphylactic shock [34,37,38].”
BackgroundNonclinical safety evaluation of a novel ionizable lipid for mRNA delivery
Broudic, K., Amberg, A., Schaefer, M. K., Spirkl, H.-P., Bernard, M., & Désert, P. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.116143 · Cited by 25
Recent advances in the targeting of systemically administered non-viral gene delivery systems
Khalil, I. A., Sato, Y., & Harashima, H. (2019) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2019.1656196 · Cited by 22
Raoufi, E., Bahramimeimandi, B., Salehi‐Shadkami, M., Chaosri, P., & Mozafari, M. R. (2021) · Biomedicines · doi:10.3390/biomedicines9050520 · Cited by 22
“Even though the membrane disruptive features of the lipid molecules improve the delivery efficiency, certain synthetic materials may cause side effects in vivo [115].”
BackgroundMaterial Design for Next-Generation mRNA Vaccines Using Lipid Nanoparticles
Higuchi, A., Sung, T., Wang, T., Ling, Q., Kumar, S. S., Hsu, S.-T., & Umezawa, A. (2022) · Journal of macromolecular science. Part C, Reviews in macromolecular chemistry and physics/Journal of macromolecular science. Reviews in macromolecular chemistry and physics · doi:10.1080/15583724.2022.2106490 · Cited by 21
“Several researchers([34,48,80,83,97,98,142]) selected MC3 (DLin-MC3-DMA in Figure 12) as an ionizable lipid on mRNA-entrapped LNPs.”
BackgroundDu, X., Yada, E., Terai, Y., Takahashi, T., Nakanishi, H., Tanaka, H., Akita, H., & Itaka, K. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15092291 · Cited by 21
“To further determine whether polyplex nanomicelle or LNP could cause hepatic and renal toxicity, we analyzed blood biochemical markers associated with liver and kidney injury [38,39], since previous studies have reported an increase in liver enzymes such as the alanine aminotransferase (ALT) and aspartate aminotransfe…”
Background
Metadata
- Authors
- Sedic, M., Senn, J. J., Lynn, A., Laska, M., Smith, M., Platz, S. J., Bolen, J., Hoge, S., Bulychev, A., Jacquinet, E., Bartlett, V., & Smith, P. F.
- Affiliations
- Moderna Therapeutics (United States) (US)
- AstraZeneca, Melbourn, Royston, UK
- PureTech (United States) (US)
- Akcea Therapeutics, Cambridge, MA
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Senn, Joseph J.
- Venue
- Veterinary Pathology
- Publisher
- SAGE Publications
- Published
- 2017-11-30
- Volume
- 55
- Issue
- 2
- Pages
- 341-354
- ISSN
- 0300-9858 (ISSN-L)
- 1544-2217
- OpenAlex
- W2774359469
- Semantic Scholar
- ff6e62a333b9a5177911689bb2e6b1d42baa1047
- Cited by
- 195
- References
- 29
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 29 · 2023: 36 · 2022: 36 · 2021: 23 · 2020: 13 · 2019: 10 · 2018: 6
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Veterinary Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Moderna
- 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 › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- modified mRNA, human erythropoietin, intravenous infusion, hematopoiesis, splenic necrosis, lymphocyte depletion, complement activation, CXCL10, liver injury, coagulation parameters, nonclinical safety evaluation
- MeSH terms
- Animals, Blood Coagulation, Erythropoietin, Female, Hematopoiesis, Infusions, Intravenous, Leukocyte Count, Lipids, Macaca fascicularis, Male, RNA, Messenger, Rats, Sprague-Dawley, Rats, Nanoparticles
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