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Despite the inclusion of N1-methyl-pseudouridine (N1m\u0470)-modified mRNA in approved coronavirus 2019 (COVID-19) vaccines and the various ongoing clinical studies with both N1m\u0470-modified and unmodified mRNA therapeutics, there are limited nonclinical data directly comparing unmodified and N1m\u0470-modified mRNA safety and tolerability. Here we present data from a repeat-dose toxicity study in Wistar Han rats, which were intramuscularly administered mRNA (either with unmodified or N1m\u0470-modified nucleosides) encapsulated into lipid nanoparticles (LNPs). The study evaluated systemic toxicity, local tolerance, and immune responses after once-weekly intramuscular injections for 3 weeks, followed by a final injection 2 weeks later. Additionally, a subgroup of animals was maintained for a 2-week dose-free period following the last dose to assess recovery from any findings. Repeat IM administration of unmodified and N1m\u0470-modified mRNA rabies vaccine to male and female Wistar Han rats was well tolerated at doses of 10\u00a0\u03bcg and 40\u00a0\u03bcg, with similar non-adverse findings irrespective of the test article used, confirming that the N1m\u0470 nucleoside modification does not impact the nonclinical safety of mRNA when encapsulated into the same LNP. As the field of RNA medicines evolves and matures, the ability to use existing knowledge of unmodified or N1m\u0470-modified mRNA to support mRNA therapeutic development in a nonclinical safety context will allow for a more streamlined and rapid process when developing or improving mRNA therapeutics.<\/jats:p>","DOI":"10.1177\/10915818261446630","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:19:09Z","timestamp":1781878749000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Nonclinical Safety Profiles of mRNA Therapeutics Comprising Unmodified or N1-Methyl-Pseudouridine-Modified Nucleosides Are Similar Following Repeated Administration"],"prefix":"10.1177","author":[{"given":"Albena","family":"Draycheva","sequence":"first","affiliation":[{"name":"Regulatory Affairs and Preclinical Safety Department, CureVac Netherlands B.V."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joske","family":"Millecam","sequence":"additional","affiliation":[{"name":"Regulatory Affairs and Preclinical Safety Department, CureVac Belgium SA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7577-2572","authenticated-orcid":false,"given":"Ebru","family":"Caba","sequence":"additional","affiliation":[{"name":"Regulatory Affairs and Preclinical Safety Department, CureVac Inc"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-023-00977-5"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01294-2"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07266-7"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00024"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-024-00095-3"},{"key":"e_1_3_7_7_2","unstructured":"WHO. 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