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For delivery into cells, these mRNAs are encapsulated in lipid nanoparticles and commonly incorporate modified ribonucleotides to improve stability, enhance translation and mitigate immune recognition\n                    <jats:sup>1<\/jats:sup>\n                    .\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>1<\/jats:sup>\n                    -Methylpseudouridine (m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8) has become the industry standard for synthetic mRNAs owing to its effectiveness in promoting translation and reducing immunogenicity\n                    <jats:sup>2<\/jats:sup>\n                    . However, recent studies have shown that m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8 can compromise translational fidelity, leading to errors such as premature termination and ribosomal frameshifting\n                    <jats:sup>3\u20135<\/jats:sup>\n                    . Here we reveal\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>4<\/jats:sup>\n                    -acetylcytidine (ac\n                    <jats:sup>4<\/jats:sup>\n                    C) as a functionally distinct alternative to m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8. Across cultured cell lines, primary human monocyte-derived dendritic cells and mouse liver, ac\n                    <jats:sup>4<\/jats:sup>\n                    C suppressed inflammatory responses as effectively as m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8 while driving higher protein yields. Single-molecule imaging of translation revealed broadly similar ribosome densities per mRNA for ac\n                    <jats:sup>4<\/jats:sup>\n                    C-modified and m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8-modified transcripts. However, translation elongation with m\n                    <jats:sup>1<\/jats:sup>\n                    \u03a8-modified mRNA was nearly twofold slower than with ac\n                    <jats:sup>4<\/jats:sup>\n                    C, which resulted in reduced protein output and increased ribosome collisions that further limited protein production through the engagement of quality-control pathways and +1 frameshifting. These findings underscore the importance of context in designing therapeutic mRNAs and position the translation elongation rate as a key determinant of the efficacy of modified ribonucleotides.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10729-8","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:47:24Z","timestamp":1782920844000},"page":"1034-1043","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity"],"prefix":"10.1038","volume":"656","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9482-1309","authenticated-orcid":false,"given":"Sarah","family":"Schiffers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0678-1501","authenticated-orcid":false,"given":"Blake W.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Prigge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shriya","family":"Krishna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7178-0097","authenticated-orcid":false,"given":"Yining","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishu","family":"Tyagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Beiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipto","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2872-2307","authenticated-orcid":false,"given":"Ayush","family":"Raman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorkell","family":"Andresson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4262-9988","authenticated-orcid":false,"given":"Hai-Quan","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9442-3041","authenticated-orcid":false,"given":"Bin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4942-2514","authenticated-orcid":false,"given":"Shalini","family":"Oberdoerffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"10729_CR1","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1038\/s41587-022-01491-z","volume":"40","author":"E Rohner","year":"2022","unstructured":"Rohner, E., Yang, R., Foo, K. 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