Impact of mRNA chemistry and manufacturing process on innate immune activation
Open accessAbstract
1-methyl-pseudouridine (1mΨ), synthesized by either a standard process shown to have double-stranded RNA (dsRNA) impurities or a modified process that yields a highly purified mRNA preparation. Our data demonstrate that the lowest stimulation of immune endpoints was with 1mΨ made by the modified process, while mRNA containing canonical uridine was immunostimulatory regardless of process. These findings confirm that uridine modification and the reduction of dsRNA impurities are both necessary and sufficient at controlling the immune-activating profile of therapeutic mRNA.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Moderna claimed that with modified nucleotide and dsRNA removal, both local and systemic innate immune effects upon mRNA vaccine administration can be limited to a bare minimum in mice.
“Moderna claimed that with such an approach, both local and systemic innate immune effects upon mRNA (vaccine) administration can be limited to a bare minimum in mice [37]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [37]
BNT162b2 and mRNA-1273 implement a combination of modified nucleotide 1mΨ replacement and removal of dsRNA fragments, which strongly reduces innate immune signaling in response to mRNA through decreased activation of TLR signaling and cytosolic RNA sensors.
“BNT162b2 and mRNA-1273 implement a combination of modified nucleotide 1mΨ replacement and removal of dsRNA fragments in the mRNA production process, which strongly reduces the innate immune signaling in response to mRNA through decreased activation of TLR signaling and cytosolic RNA sensors.”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [37]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
mRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667 · see citing works
Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8
Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., & Bauer, S. (2004) · Science · doi:10.1126/science.1093620 · Cited by 3,947 · see citing works
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Ishikawa, H., & Barber, G. N. (2008) · Nature · doi:10.1038/nature07317 · Cited by 3,576 · see citing works
Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., & Reis e Sousa, C. (2004) · Science · doi:10.1126/science.1093616 · Cited by 3,444 · see citing works
Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets
Sonenberg, N., & Hinnebusch, A. G. (2009) · Cell · doi:10.1016/j.cell.2009.01.042 · Cited by 3,304 · cited 4× · see citing works
“One possible outcome of immune activation is reduced mRNA translation due to feedback between the innate immune system and translation machinery, which will decrease the potency of therapeutic mRNA ( 18 , 19 ).”
InfluentialIPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K. J., Takeuchi, O., & Akira, S. (2005) · Nature Immunology · doi:10.1038/ni1243 · Cited by 2,562 · see citing works
Karikó, K., Muramatsu, H., Welsh, F. A., Ludwig, J., Kato, H., Akira, S., & Weissman, D. (2008) · Molecular Therapy · doi:10.1038/mt.2008.200 · Cited by 1,930 · see citing works
Innate immune recognition of viral infection
Kawai, T., & Akira, S. (2006) · Nature Immunology · doi:10.1038/ni1303 · Cited by 1,899 · see citing works
Karikó, K., Muramatsu, H., Ludwig, J., & Weissman, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr695 · Cited by 898 · see citing works
CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications
Liu, M., Guo, S., Hibbert, J. M., Jain, V., Singh, N., Wilson, N. O., & Stiles, J. K. (2011) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2011.06.001 · Cited by 752 · see citing works
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 · see citing works
Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation
Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Karikó, K. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq347 · Cited by 682 · see citing works
Advances 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 680 · see citing works
Bahl, K., Senn, J. J., Yuzhakov, O., Bulychev, A., Brito, L. A., Hassett, K. J., Laska, M. E., Smith, M., Almarsson, Ö., Thompson, J., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.03.035 · Cited by 642 · see citing works
Recognition of Endogenous Nucleic Acids by the Innate Immune System
Roers, A., Hiller, B., & Hornung, V. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.002 · Cited by 541 · see citing works
Thess, A., Grund, S., Mui, B. L., Hope, M. J., Baumhof, P., Fotin-Mleczek, M., & Schlake, T. (2015) · Molecular Therapy · doi:10.1038/mt.2015.103 · Cited by 513 · cited 1× · see citing works
“Although some studies suggest that purification of unmodified mRNA is sufficient to achieve effective mRNA-based therapeutics, the measures of immune stimulation reported typically included serum activation markers and protein expression levels ( 46 ).”
Feldman, R. A., Fuhr, R., Smolenov, I., (Mick) Ribeiro, A., Panther, L., Watson, M., Senn, J. J., Smith, M., Almarsson, Ӧ., Pujar, H. S., et al. (2019) · Vaccine · doi:10.1016/j.vaccine.2019.04.074 · Cited by 454 · see citing works
Double-Stranded RNA Sensors and Modulators in Innate Immunity
Hur, S. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041356 · Cited by 420 · see citing works
Toll-like receptor 8 senses degradation products of single-stranded RNA
Tanji, H., Ohto, U., Shibata, T., Taoka, M., Yamauchi, Y., Isobe, T., Miyake, K., & Shimizu, T. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2943 · Cited by 404 · see citing works
Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs
Hewitt, S. L., Bai, A., Bailey, D., Ichikawa, K., Zielinski, J., Karp, R., Apte, A., Arnold, K., Zacharek, S. J., Iliou, M. S., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aat9143 · Cited by 316 · see citing works
Self-citationSchonborn, J., Oberstraβ, J., Breyel, E., Tittgen, J., Schumacher, J., & Lukacs, N. (1991) · Nucleic Acids Research · doi:10.1093/nar/19.11.2993 · Cited by 303 · see citing works
Lazear, H. M., Lancaster, A., Wilkins, C., Suthar, M. S., Huang, A., Vick, S. C., Clepper, L., Thackray, L., Brassil, M. M., Virgin, H. W., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003118 · Cited by 296 · cited 1× · see citing works
“MAVS, an adaptor protein that activates type I IFN through transcription factors IFN regulatory factor 3 (IRF3), IRF7, and NF- B ( 27 , 28 ), is downstream of both RIG-I and MDA5 ( 17 ).”
Hartmann, G. (2017) · Advances in Immunology · doi:10.1016/bs.ai.2016.11.001 · Cited by 285 · see citing works
Boosting intracellular delivery of lipid nanoparticle-encapsulated mRNA
Patel, S., Ashwanikumar, N., Robinson, E., DuRoss, A., Sun, C., Murphy-Benenato, K. E., Mihai, C., Almarsson, Ö., & Sahay, G. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b02664 · Cited by 251 · see citing works
Durbin, A. F., Wang, C., Marcotrigiano, J., & Gehrke, L. (2016) · mBio · doi:10.1128/mbio.00833-16 · Cited by 238 · see citing works
RIG-I Forms Signaling-Competent Filaments in an ATP-Dependent, Ubiquitin-Independent Manner
Peisley, A., Wu, B., Yao, H., Walz, T., & Hur, S. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.024 · Cited by 236 · see citing works
An origin of the immunogenicity of in vitro transcribed RNA
Mu, X., Greenwald, E., Ahmad, S., & Hur, S. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky177 · Cited by 218 · see citing works
Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
Gan, L., Fermer, M. L., Carlsson, L. G., Arfvidsson, C., Egnell, A., Rudvik, A., Kjaer, M., Collén, A., Thompson, J. D., Joyal, J. L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08852-4 · Cited by 209 · see citing works
Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: Key regulators of innate immunity
Barral, P. M., Sarkar, D., Su, Z.-Z., Barber, G. N., DeSalle, R., Racaniello, V. R., & Fisher, P. B. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.06.012 · Cited by 200 · see citing works
Collaboration between the innate immune receptors dectin‐1, TLRs, and Nods
Underhill, D. M. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00548.x · Cited by 187 · see citing works
RNA template-directed RNA synthesis by T7 RNA polymerase.
Cazenave, C., & Uhlenbeck, O. C. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.15.6972 · Cited by 170 · see citing works
Foster, J., Choudhari, N., Perazzelli, J., Storm, J., Hofmann, T. J., Jain, P., Storm, P. B., Pardi, N., Weissman, D., Waanders, A. J., et al. (2018) · Human Gene Therapy · doi:10.1089/hum.2018.145 · Cited by 133 · see citing works
Palchetti, S., Starace, D., Cesaris, P. D., Filippini, A., Elio Ziparo, A., & Anna Riccioli, A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.601625 · Cited by 124 · see citing works
TLR Cross-talk Confers Specificity to Innate Immunity
Tan, R. S. T., Ho, B., Leung, B. P. L., & Ding, J. L. (2014) · International Reviews of Immunology · doi:10.3109/08830185.2014.921164 · Cited by 122 · see citing works
Messenger RNA therapy for rare genetic metabolic diseases
Berraondo, P., Martini, P. G. V., Avila, M. A., & Fontanellas, A. (2019) · Gut · doi:10.1136/gutjnl-2019-318269 · Cited by 118 · see citing works
Evading innate immunity in nonviral mRNA delivery: don't shoot the messenger.
Devoldere, J., Dewitte, H., De Smedt, S. C., & Remaut, K. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2015.07.009 · Cited by 112 · see citing works
A minimal RNA ligand for potent RIG-I activation in living mice
Linehan, M. M., Dickey, T. H., Molinari, E., Fitzgerald, M. E., Potapova, O., Iwasaki, A., & Pyle, A. M. (2018) · Science Advances · doi:10.1126/sciadv.1701854 · Cited by 111 · see citing works
Besin, G., Milton, J., Sabnis, S., Howell, R. D., Mihai, C., Burke, K. E., Benenato, K. E., Stanton, M., Smith, P., Senn, J. J., et al. (2019) · ImmunoHorizons · doi:10.4049/immunohorizons.1900029 · Cited by 108 · see citing works
The Emerging Role of In Vitro-Transcribed mRNA in Adoptive T Cell Immunotherapy
Foster, J., Barrett, D. M., & Karikó, K. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.01.018 · Cited by 98 · see citing works
The RNase III Family: A Conserved Structure and Expanding Functions in Eukaryotic dsRNA Metabolism
Lamontagne, B., Larose, S., Boulanger, J., & Elela, S. A. (2001) · Current Issues in Molecular Biology · doi:10.21775/cimb.003.071 · Cited by 97 · see citing works
RIG-I-Mediated STING Upregulation Restricts Herpes Simplex Virus 1 Infection
Liu, Y., Goulet, M.-L., Sze, A., Hadj, S. B., Belgnaoui, S. M., Lababidi, R. R., Zheng, C., Fritz, J. H., Olagnier, D. P., & Lin, R. (2016) · Journal of Virology · doi:10.1128/jvi.00748-16 · Cited by 84 · see citing works
Vallazza, B., Petri, S., Poleganov, M. A., Eberle, F., Kuhn, A. N., & Şahin, U. (2015) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1288 · Cited by 73 · see citing works
Essential Role of the N-terminal Domain in the Regulation of RIG-I ATPase Activity
Gee, P., Chua, P. K., Gevorkyan, J., Klumpp, K., Nájera, I., Swinney, D. C., & Deval, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706777200 · Cited by 67 · see citing works
Dauletbaev, N., Cammisano, M., Herscovitch, K., & Lands, L. C. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1400840 · Cited by 59 · see citing works
Optimizing Modified mRNA In Vitro Synthesis Protocol for Heart Gene Therapy
Hadas, Y., Sultana, N., Youssef, E., Sharkar, M. T. K., Kaur, K., Chepurko, E., & Zangi, L. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.07.006 · Cited by 41 · see citing works
Unusual promoter-independent transcription reactions with bacteriophage RNA polymerases
Krupp, G. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.8.3023 · Cited by 37 · see citing works
Sadik, C. D., Bachmann, M., Pfeilschifter, J. M., & Mühl, H. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp525 · Cited by 31 · see citing works
Messenger RNA as a Novel Therapeutic Approach
Stanton, M. G., & Murphy-Benenato, K. E. (2017) · Topics in medicinal chemistry · doi:10.1007/7355_2016_30 · Cited by 16 · see citing works
RNA Technologies Expand Tool Kit for Cancer Immunotherapy
(2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-nd2019-009 · Cited by 3 · see citing works
Hoerr, I. (2000) · doi:10.1002/1521-4141(200001)30:1
Flagged first, then by citations
1 of the 51 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness
Corbett, K. S., Edwards, D. K., Leist, S. R., Abiona, O. M., Boyoglu-Barnum, S., Gillespie, R. A., Himansu, S., Schäfer, A., Ziwawo, C. T., DiPiazza, A. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2622-0 · Cited by 1,615 · see citing works
Unlocking the promise of mRNA therapeutics
Rohner, E., Yang, R., Foo, K. S., Goedel, A., & Chien, K. R. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01491-z · Cited by 612 · see citing works
IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines
Tahtinen, S., Tong, A.-J., Himmels, P., Oh, J., Paler-Martinez, A., Kim, L., Wichner, S., Oei, Y., McCarron, M. J., Freund, E. C., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01160-y · Cited by 535 · see citing works
Innate immune mechanisms of mRNA vaccines
Verbeke, R., Hogan, M. J., Loré, K., & Pardi, N. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.014 · Cited by 518 · see citing works
The dawn of mRNA vaccines: the COVID-19 case
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.03.043 · Cited by 504 · see citing works
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 · see citing works
Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines
Nance, K. D., & Meier, J. L. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00197 · Cited by 466 · see citing works
Targeting cancer with mRNA–lipid nanoparticles: key considerations and future prospects
Kon, E., Ad‐El, N., Hazan‐Halevy, I., Stotsky‐Oterin, L., & Peer, D. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00811-9 · Cited by 385 · see citing works
Impact of lipid nanoparticle size on mRNA vaccine immunogenicity
Hassett, K. J., Higgins, J. S., Woods, A., Levy, B., Xia, Y., Hsiao, C. J., Acosta, E. P., Almarsson, Ö., Moore, M. J., & Brito, L. A. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.05.021 · Cited by 373 · see citing works
Heinz, F. X., & Stiasny, K. (2021) · npj Vaccines · doi:10.1038/s41541-021-00369-6 · Cited by 362 · see citing works
Novel approaches for vaccine development
Gebre, M. S., Brito, L. A., Tostanoski, L. H., Edwards, D. K., Carfi, A., & Barouch, D. H. (2021) · Cell · doi:10.1016/j.cell.2021.02.030 · Cited by 347 · see citing works
Nucleic acid delivery for therapeutic applications
Gupta, A., Andresen, J. L., Manan, R. S., & Langer, R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113834 · Cited by 339 · see citing works
Suzuki, Y., & Ishihara, H. (2021) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2021.100424 · Cited by 304 · see citing works
A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems
Packer, M., Gyawali, D., Yerabolu, R., Schariter, J., & White, P. (2021) · Nature Communications · doi:10.1038/s41467-021-26926-0 · Cited by 279 · see citing works
The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines
Morais, P., Adachi, H., & Yu, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.789427 · Cited by 274 · see citing works
An engineered T7 RNA polymerase that produces mRNA free of immunostimulatory byproducts
Dousis, A. D., Ravichandran, K. R., Hobert, E. M., Moore, M. J., & Rabideau, A. E. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01525-6 · Cited by 238 · see citing works
mRNA vaccines for infectious diseases — advances, challenges and opportunities
Pardi, N., & Krammer, F. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01042-y · Cited by 246 · see citing works
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 237 · see citing works
The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case
Blenke, E. O., Örnskov, E., Schöneich, C., Nilsson, G. Å., Volkin, D. B., Mastrobattista, E., Almarsson, Ö., & Crommelin, D. J. A. (2022) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2022.11.001 · Cited by 214 · see citing works
August, A., Attarwala, H. Z., Himansu, S., Kalidindi, S., Lu, S., Pajón, R., Han, S., Lecerf, J., Tomassini, J. E., Hard, M., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01573-6 · Cited by 199 · see citing works
Scheaffer, S. M., Lee, D., Whitener, B., Ying, B., Wu, K., Liang, C.-Y., Jani, H., Martin, P., Amato, N. J., Avena, L. E., et al. (2023) · Nature Medicine · doi:10.1038/s41591-022-02092-8 · Cited by 169 · see citing works
Zhang, P., Narayanan, E., Liu, Q., Tsybovsky, Y., Boswell, K. L., Ding, S., Hu, Z., Follmann, D. A., Lin, Y., Miao, H., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01574-5 · Cited by 164 · see citing works
Minnaert, A.-K., Vanluchene, H., Verbeke, R., Lentacker, I., De Smedt, S. C., Raemdonck, K., Sanders, N. N., & Remaut, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113900 · Cited by 157 · see citing works
Species-agnostic polymeric formulations for inhalable messenger RNA delivery to the lung
Rotolo, L., Vanover, D. A., Bruno, N. C., Peck, H. E., Zurla, C., Murray, J., Noel, R. K., O’Farrell, L., Araínga, M., Orr‐Burks, N., et al. (2022) · Nature Materials · doi:10.1038/s41563-022-01404-0 · Cited by 157 · see citing works
Tailor made: the art of therapeutic mRNA design
Metkar, M., Pepin, C. S., & Moore, M. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00827-x · Cited by 153 · see citing works
Non-viral delivery of the CRISPR/Cas system: DNA versus RNA versus RNP
Lin, Y., Wagner, E., & Lächelt, U. (2022) · Biomaterials Science · doi:10.1039/d1bm01658j · Cited by 141 · see citing works
Immunogenicity of In Vitro -Transcribed RNA
Mu, X. N., & Hur, S. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00521 · Cited by 138 · see citing works
Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines
Rijkers, G. T., Weterings, N., Obregón‐Henao, A., Dutt, T., Dutt, T. S., van Overveld, F. J., & Henao-Tamayo, M. I. (2021) · Vaccines · doi:10.3390/vaccines9080848 · Cited by 134 · see citing works
mRNA vaccine trafficking and resulting protein expression after intramuscular administration
Hassett, K. J., Rajlic, I. L., Bahl, K., White, R. A., Cowens, K. B., Jacquinet, E., & Burke, K. E. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.102083 · Cited by 125 · see citing works
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 128 · see citing works
Gainor, J. F., Patel, M. R., Weber, J. S., Gutierrez, M., Bauman, J. E., Clarke, J. M., Julian, R., Scott, A. J., Geiger, J. L., Kirtane, K., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0158 · Cited by 124 · see citing works
Self-citationMicrofluidic fabrication of lipid nanoparticles for the delivery of nucleic acids
Prakash, G., Shokr, A., Willemen, N. G. A., Bashir, S. M., Shin, S. R., & Hassan, S. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114197 · Cited by 117 · see citing works
Ly, H. H., Daniel, S., Soriano, S. K. V., Kis, Z., & Blakney, A. K. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.2c00032 · Cited by 116 · see citing works
Mackin, S., Desai, P., Whitener, B. M., Karl, C. E., Liu, M., Baric, R. S., Edwards, D. K., Chicz, T. M., McNamara, R. P., Alter, G., et al. (2023) · Nature Microbiology · doi:10.1038/s41564-023-01359-1 · Cited by 114 · see citing works
Esprit, A., de Mey, W., Shahi, R. B., Thielemans, K., Franceschini, L., & Breckpot, K. (2020) · Vaccines · doi:10.3390/vaccines8040776 · Cited by 105 · see citing works
mRNA-Based Cancer Vaccines: A Therapeutic Strategy for the Treatment of Melanoma Patients
Bidram, M., Zhao, Y., Shebardina, N. G., Baldin, A. V., Bazhin, A. V., Ganjalikhany, M. R., Zamyatnin, A. A., & Ganjalıkhani-Hakemi, M. (2021) · Vaccines · doi:10.3390/vaccines9101060 · Cited by 106 · see citing works
Current Developments and Challenges of mRNA Vaccines
Chen, J., Chen, J., & Xu, Q. (2022) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-110220-031722 · Cited by 106 · see citing works
On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device
Okuda, K., Sato, Y., Iwakawa, K., Sasaki, K., Okabe, N., Maeki, M., Tokeshi, M., & Harashima, H. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.06.017 · Cited by 96 · see citing works
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 102 · see citing works
The Pivotal Role of Chemical Modifications in mRNA Therapeutics
Liu, A., & Wang, X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.901510 · Cited by 97 · see citing works
RNA chemistry and therapeutics
Wang, S., Weissman, D., & Dong, Y. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01237-x · Cited by 98 · see citing works
The competitive landscape of the dsRNA world
Cottrell, K. A., Andrews, R. J., & Bass, B. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.11.033 · Cited by 87 · see citing works
Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice
Ying, B., Scheaffer, S. M., Whitener, B. M., Liang, C.-Y., Dmytrenko, O., Mackin, S., Wu, K., Lee, D. W., Avena, L. E., Chong, Z., et al. (2022) · Cell · doi:10.1016/j.cell.2022.03.037 · Cited by 105 · see citing works
August, A., Shaw, C. A., Lee, H. R., Knightly, C., Kalidindia, S., Chu, L., Essink, B. J., Seger, W., Zaks, T. Z., Smolenov, I. V., et al. (2022) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofac206 · Cited by 90 · see citing works
A Biopharmaceutical Perspective on Higher-Order Structure and Thermal Stability of mRNA Vaccines
Kloczewiak, M. A., Banks, J. M., Jin, L., & Brader, M. L. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.2c00092 · Cited by 89 · see citing works
Intracellular Protein Delivery: Approaches, Challenges, and Clinical Applications
Chan, A., & Tsourkas, A. (2023) · BME Frontiers · doi:10.34133/bmef.0035 · Cited by 90 · see citing works
Advancements in mRNA Encoded Antibodies for Passive Immunotherapy
Deal, C. E., Carfı́, A., & Plante, O. J. (2021) · Vaccines · doi:10.3390/vaccines9020108 · Cited by 87 · see citing works
mRNA Vaccine Development for Emerging Animal and Zoonotic Diseases
Le, T., Sun, C., Chang, J., Zhang, G., & Yin, X. (2022) · Viruses · doi:10.3390/v14020401 · Cited by 93 · see citing works
Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains
Ying, B., Whitener, B., VanBlargan, L. A., Hassan, A. O., Shrihari, S., Liang, C.-Y., Karl, C. E., Mackin, S., Chen, R. E., Kafai, N. M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abm3302 · Cited by 85 · see citing works
mRNA in cancer immunotherapy: beyond a source of antigen
Hoecke, L. V., Verbeke, R., Dewitte, H., Lentacker, I., Vermaelen, K. Y., Breckpot, K., & Lint, S. V. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01329-3 · Cited by 80 · see citing works
Cui, L., Hunter, M. R., Sonzini, S., Pereira, S. G. T., Romanelli, S. M., Liu, K., Li, W., Liang, L., Yang, B., Mahmoudi, N., et al. (2021) · Small · doi:10.1002/smll.202105832 · Cited by 78 · see citing works
Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy
Duan, L.-J., Wang, Q., Zhang, C., Yang, D.-X., & Zhang, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.923647 · Cited by 79 · see citing works
Moradian, H., Roch, T., Anthofer, L., Lendlein, A., & Gossen, M. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.01.004 · Cited by 75 · see citing works
Self-Amplifying RNA Vaccine Candidates: Alternative Platforms for mRNA Vaccine Development
Schmidt, C., & Schnierle, B. S. (2023) · Pathogens · doi:10.3390/pathogens12010138 · Cited by 78 · see citing works
mRNA-Loaded Lipid Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy
Sasaki, K., Sato, Y., Okuda, K., Iwakawa, K., & Harashima, H. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14081572 · Cited by 78 · see citing works
Chaturvedi, S., Vasen, G., Pablo, M., Chen, X., Beutler, N., Kumar, A. J., Tanner, E. J., Illouz, S., Rahgoshay, D., Burnett, J. C., et al. (2021) · Cell · doi:10.1016/j.cell.2021.11.004 · Cited by 72 · see citing works
Double-stranded RNA reduction by chaotropic agents during in vitro transcription of messenger RNA
Piao, X., Yadav, V., Wang, E., Chang, W., Tau, L., Lindenmuth, B. E., & Wang, S. X. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.08.001 · Cited by 73 · see citing works
tRNA therapeutics for genetic diseases
Coller, J. M., & Ignatova, Z. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00829-9 · Cited by 72 · see citing works
An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection
Bollman, B. A., Nunna, N., Bahl, K., Hsiao, C. J., Bennett, H., Butler, S., Foreman, B. M., Burgomaster, K. E., Aleshnick, M., Kong, W., et al. (2023) · npj Vaccines · doi:10.1038/s41541-023-00656-4 · Cited by 72 · see citing works
Maximizing mRNA vaccine production with Bayesian optimization
Rosa, S. S., Nunes, D., Antunes, L., Prazeres, D. M. F., Marques, M. P. C., & Azevedo, A. M. (2022) · Biotechnology and Bioengineering · doi:10.1002/bit.28216 · Cited by 70 · see citing works
Loomis, R. J., DiPiazza, A. T., Falcone, S., Ruckwardt, T. J., Morabito, K. M., Abiona, O. M., Chang, L. A., Caringal, R. T., Presnyak, V., Narayanan, E., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.772864 · Cited by 70 · see citing works
TLRs: Innate Immune Sentries against SARS-CoV-2 Infection
Mantovani, S., Oliviero, B., Varchetta, S., Renieri, A., & Mondelli, M. U. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098065 · Cited by 70 · see citing works
Cao, J.-S., Choi, M., Guadagnin, E., Soty, M., Silva, M., Verzieux, V., Weisser, E., Markel, A., Zhuo, J., Liang, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23318-2 · Cited by 58 · see citing works
Bicknell, A. A., Reid, D. W., Licata, M. C., Jones, A. K., Cheng, Y. M., Li, M., Hsiao, C. J., Pepin, C. S., Metkar, M., Levdansky, Y., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114098 · Cited by 68 · see citing works
Review of machine learning for lipid nanoparticle formulation and process development
Dorsey, P. J., Lau, C. L., Chang, T., Doerschuk, P. C., & D’Addio, S. M. (2024) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2024.09.015 · Cited by 73 · see citing works
A general temperature-guided language model to design proteins of enhanced stability and activity
Jiang, F., Li, M.-C., Dong, J., Yu, Y.-X., Sun, X., Wu, B., Huang, J., Kang, L.-Q., Pei, Y., Zhang, L., et al. (2024) · Science Advances · doi:10.1126/sciadv.adr2641 · Cited by 64 · see citing works
mRNA-Based Therapeutics in Cancer Treatment
Sun, H., Zhang, Y., Wang, G., Yang, W., & Xu, Y. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15020622 · Cited by 63 · see citing works
de Picciotto, S., DeVita, N., Hsiao, C. J., Honan, C., Tse, S., Nguyen, M., Ferrari, J. D., Zheng, W., Wipke, B. T., & Huang, E. (2022) · Nature Communications · doi:10.1038/s41467-022-31130-9 · Cited by 60 · see citing works
Baek, R. C., Coughlan, K. A., Jiang, L., Liang, M., Ci, L., Singh, H., Zhang, H., Kaushal, N., Rajlic, I. L., Van, L. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47460-9 · Cited by 61 · see citing works
Development and applications of mRNA treatment based on lipid nanoparticles
Wang, Z., Ma, W., Fu, X., Qi, Y., Zhao, Y., & Zhang, S. (2023) · Biotechnology Advances · doi:10.1016/j.biotechadv.2023.108130 · Cited by 57 · see citing works
van Dülmen, M., Muthmann, N., & Rentmeister, A. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202100352 · Cited by 54 · see citing works
A Review on the Stability Challenges of Advanced Biologic Therapeutics
Sarvepalli, S., Pasika, S. R., Verma, V., Thumma, A., Bolla, S., Nukala, P. K., Butreddy, A., & Bolla, P. K. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17050550 · Cited by 58 · see citing works
Olson, K. E., Namminga, K. L., Lu, Y., Thurston, M. J., Schwab, A. D., de Picciotto, S., Tse, S., Walker, W., Iacovelli, J., Small, C. G., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.120786 · Cited by 56 · see citing works
Targeting the undruggable oncogenic KRAS: the dawn of hope
Asimgil, H., Ertetik, U., Çevik, N. C., Ekizce, M., Doğruöz, A., Gökalp, M., Sever, E. A., Istvánffy, R., Friess, H., Ceyhan, G. O., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.153688 · Cited by 55 · see citing works
Research progress on circular RNA vaccines
Bai, Y., Liu, D., He, Q., Liu, J., Mao, Q., & Liang, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1091797 · Cited by 58 · see citing works
Jian, F., Wec, A. Z., Feng, L., Yu, Y., Wang, L., Wang, P., Yu, L., Wang, J., Hou, J., Berrueta, D. M., et al. (2025) · Nature Microbiology · doi:10.1038/s41564-025-02030-7 · Cited by 56 · see citing works
mRNA vaccine designs for optimal adjuvanticity and delivery
Mochida, Y., & Uchida, S. (2024) · RNA Biology · doi:10.1080/15476286.2024.2333123 · Cited by 55 · see citing works
mRNA vaccines: a new era in vaccine development
Chandra, S., Wilson, J. C., Good, D. M., & Wei, M. Q. (2024) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.32604/or.2024.043987 · Cited by 58 · see citing works
Optimized circular RNA vaccines for superior cancer immunotherapy
Yu, H., Wen, Y., Yu, W., Lu, L., Yang, Y., Liu, C., Hu, Z., Fang, Z., & Huang, S. (2024) · Theranostics · doi:10.7150/thno.104698 · Cited by 52 · see citing works
High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications
Seo, H., Jeon, L., Kwon, J., & Lee, H. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202203033 · Cited by 51 · see citing works
An Update on mRNA-Based Viral Vaccines
Jeeva, S., Kim, K., Shin, C. H., Wang, B., & Kang, S. (2021) · Vaccines · doi:10.3390/vaccines9090965 · Cited by 49 · see citing works
Analysis of therapeutic nucleic acids by capillary electrophoresis
Wei, B., Goyon, A., & Zhang, K. (2022) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2022.114928 · Cited by 50 · see citing works
Mirtaleb, M. S., Falak, R., Heshmatnia, J., Bakhshandeh, B., Taheri, R. A., Soleimanjahi, H., & Emameh, R. Z. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109934 · Cited by 51 · see citing works
Messenger RNA chromatographic purification: advances and challenges
Xue, F., Su, Z. G., Cheng, Y., Ma, G., & Zhang, S. (2023) · Journal of Chromatography A · doi:10.1016/j.chroma.2023.464321 · Cited by 49 · see citing works
Comprehensive analysis of lipid nanoparticle formulation and preparation for RNA delivery
Haque, M. A., Shrestha, A., Mikelis, C. M., & Mattheolabakis, G. (2024) · International Journal of Pharmaceutics X · doi:10.1016/j.ijpx.2024.100283 · Cited by 49 · see citing works
Human type I IFN deficiency does not impair B cell response to SARS-CoV-2 mRNA vaccination
Sokal, A., Bastard, P., Chappert, P., Spaeth, G. B., Fourati, S., Vandenberghe, A., Lagouge-Roussey, P., Meyts, I., Gervais, A., Bouvier‐Alias, M., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220258 · Cited by 48 · see citing works
The Dual Role of the Innate Immune System in the Effectiveness of mRNA Therapeutics
Muslimov, A. R., Tereshchenko, V., Shevyrev, D., Rogova, A. S., Lepik, K. V., Reshetnikov, V. V., & Ivanov, R. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914820 · Cited by 50 · see citing works
Kubara, K., Yamazaki, K., Miyazaki, T., Kondo, K., Kurotaki, D., Tamura, T., & Suzuki, Y. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.01.020 · Cited by 50 · see citing works
Stewart-Jones, G., Elbashir, S. M., Wu, K., Lee, D., Renzi, I., Ying, B., Koch, M., Sein, C. E., Choi, A., Whitener, B. M., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf4100 · Cited by 51 · see citing works
Aptamer-based assembly systems for SARS-CoV-2 detection and therapeutics
Dong, Y., Wang, J., Chen, L., Chen, H., Dang, S., & Li, F. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00774j · Cited by 46 · see citing works
Nanotechnology-enabled immunoengineering approaches to advance therapeutic applications
Chuang, S. T., Conklin, B., Stein, J. B., Pan, G., & Lee, K. (2022) · Nano Convergence · doi:10.1186/s40580-022-00310-0 · Cited by 48 · see citing works
Self-amplifying mRNA-Based Vaccine Technology and Its Mode of Action
Maruggi, G., Ulmer, J. B., Rappuoli, R., & Yu, D. L. (2021) · Current topics in microbiology and immunology · doi:10.1007/82_2021_233 · Cited by 45 · see citing works
Lipid nanoparticle (LNP) mediated mRNA delivery in neurodegenerative diseases
Moosavi, S. G., Rahiman, N., Jaafari, M. R., & Arabi, L. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.113641 · Cited by 52 · see citing works
miRNA effects on gut homeostasis: therapeutic implications for inflammatory bowel disease
Dhuppar, S., & Murugaiyan, G. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.09.003 · Cited by 46 · see citing works
Eftekhari, Z., Zohrabi, H., Oghalaie, A., Ebrahimi, T., Shariati, F. S., Behdani, M., & Kazemi‐Lomedasht, F. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102313 · Cited by 43 · see citing works
Lazaros, G. A., Klein, A. L., Hatziantoniou, S., Tsioufis, C. P., Tsakris, A., & Anastassopoulou, C. G. (2021) · Vaccine · doi:10.1016/j.vaccine.2021.07.016 · Cited by 41 · see citing works
N1-methyl-pseudouridine is incorporated with higher fidelity than pseudouridine in synthetic RNAs
Chen, T.-H., Potapov, V., Dai, N., Ong, J. L., & Roy, B. (2022) · Scientific Reports · doi:10.1038/s41598-022-17249-1 · Cited by 43 · see citing works
Therapeutic synthetic and natural materials for immunoengineering
Slezak, A., Chang, K., Hossainy, S., Mansurov, A., Rowan, S. J., Hubbell, J. A., & Guler, M. O. (2024) · Chemical Society Reviews · doi:10.1039/d3cs00805c · Cited by 44 · see citing works
Miller, M. G., Alvizo, O., Baskerville, S., Chintala, A., Chng, C., Dassie, J. P., Dorigatti, J. D., Huisman, G. W., Jenne, S., Kadam, S., et al. (2024) · Faraday Discussions · doi:10.1039/d4fd00023d · Cited by 40 · see citing works
- Authors
- Nelson, J., Sorensen, E. W., Mintri, S., Rabideau, A. E., Zheng, W., Besin, G., Khatwani, N., Su, S. V., Miracco, E. J., Issa, W. J., Hoge, S., Stanton, M. G., & Joyal, J. L.
- Affiliations
- Moderna Inc., 200 Technology Square, Cambridge, MA, USA.
- Corresponding author
- Joyal, John L.
- ORCID
- Venue
- Science Advances
- Published
- 2020-06-26
- Volume
- 6
- Issue
- 26
- Pages
- eaaz6893-eaaz6893
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC7314518
- OpenAlex
- W3037578051
- Cited by
- 354
- References
- 51
- Citations by year
- 2026: 51 · 2025: 57 · 2024: 66 · 2023: 59 · 2022: 74 · 2021: 44 · 2020: 2
- FWCI
- 14.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Moderna, Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- mRNA vaccines, production process, innate immune activation, immune enhancement
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
