美国国家癌症研究所Shalini Oberdoerffer课题组在研究中取得进展。他们认为N4-乙酰胞苷提高合成mRNA的翻译率和保真度。2026年7月1日出版的《自然》发表了这项成果。
在这里，该团队揭示了N4-乙酰胞苷（ac4C）作为m1Ψ的功能不同的替代品。在培养的细胞系中，原代人单核细胞衍生的树突状细胞和无主题肝脏，ac4C抑制炎症反应与m1Ψ一样有效，同时驱动更高的蛋白质产量。翻译的单分子成像显示ac4C修饰和m1Ψ修饰转录本的每mRNA核糖体密度大致相似。
然而，m1Ψ修饰 mRNA的翻译延伸率比ac4C慢近两倍，这导致蛋白质输出减少，核糖体碰撞增加，通过质量控制途径和+1帧移位进一步限制了蛋白质的产生。这些发现强调了环境在设计治疗性mRNA中的重要性，并将翻译延伸率定位为修饰核糖核苷酸有效性的关键决定因素。
据悉，合成mRNA疗法为治疗包括癌症和感染性疾病在内的各种疾病提供了一个通用的平台。为了进入细胞，这些mRNA被包裹在脂质纳米颗粒中，通常包含修饰的核糖核苷酸，以提高稳定性，增强翻译和减轻免疫识别。N1-甲基假二吡啶（m1Ψ）由于其促进翻译和降低免疫原性的有效性，已成为合成mRNA的行业标准。然而，最近的研究表明m1Ψ会损害翻译保真度，导致诸如过早终止和核糖体移框等错误。
附：英文原文
Title: N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity
Author: Schiffers, Sarah, Nelson, Blake W., Prigge, Maria, Krishna, Shriya, Watkins, Leslie, Zhu, Yining, Tyagi, Nishu, Beiki, Hamid, Das, Sudipto, Raman, Ayush, Ma, Jingyao, Andresson, Thorkell, Mao, Hai-Quan, Wu, Bin, Oberdoerffer, Shalini
Issue&Volume: 2026-07-01
Abstract: Synthetic mRNA therapeutics offer a versatile platform for treating diverse conditions, including cancer and infectious diseases. For delivery into cells, these mRNAs are encapsulated in lipid nanoparticles and commonly incorporate modified ribonucleotides to improve stability, enhance translation and mitigate immune recognition1. N1-Methylpseudouridine (m1Ψ) has become the industry standard for synthetic mRNAs owing to its effectiveness in promoting translation and reducing immunogenicity2. However, recent studies have shown that m1Ψ can compromise translational fidelity, leading to errors such as premature termination and ribosomal frameshifting3,4,5. Here we reveal N4-acetylcytidine (ac4C) as a functionally distinct alternative to m1Ψ. Across cultured cell lines, primary human monocyte-derived dendritic cells and mouse liver, ac4C suppressed inflammatory responses as effectively as m1Ψ while driving higher protein yields. Single-molecule imaging of translation revealed broadly similar ribosome densities per mRNA for ac4C-modified and m1Ψ-modified transcripts. However, translation elongation with m1Ψ-modified mRNA was nearly twofold slower than with ac4C, 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.
DOI: 10.1038/s41586-026-10729-8
Source: https://www.nature.com/articles/s41586-026-10729-8
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html