Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

IF 41.7 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Nature biotechnology Pub Date : 2024-03-22 DOI:10.1038/s41587-024-02174-7

Hongyu Chen, Dangliang Liu, Jianting Guo, Abhishek Aditham, Yiming Zhou, Jiakun Tian, Shuchen Luo, Jingyi Ren, Alvin Hsu, Jiahao Huang, Franklin Kostas, Mingrui Wu, David R. Liu, Xiao Wang

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Abstract

Although messenger RNA (mRNA) has proved effective as a vaccine, its potential as a general therapeutic modality is limited by its instability and low translation capacity. To increase the duration and level of protein expression from mRNA, we designed and synthesized topologically and chemically modified mRNAs with multiple synthetic poly(A) tails. Here we demonstrate that the optimized multitailed mRNA yielded ~4.7–19.5-fold higher luminescence signals than the control mRNA from 24 to 72 h post transfection in cellulo and 14 days detectable signal versus <7 days signal from the control in vivo. We further achieve efficient multiplexed genome editing of the clinically relevant genes Pcsk9 and Angptl3 in mouse liver at a minimal mRNA dosage. Taken together, these results provide a generalizable approach to synthesize capped branched mRNA with markedly enhanced translation capacity. mRNA with engineered poly(A) tails produces prolonged higher levels of protein.

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经化学修饰的多聚（A）支链可提高 mRNA 的翻译能力。

尽管信使核糖核酸（mRNA）已被证明可以有效地用作疫苗，但由于其不稳定性和较低的翻译能力，其作为一般治疗方法的潜力受到了限制。为了增加 mRNA 蛋白表达的持续时间和水平，我们设计并合成了具有多个合成聚（A）尾的拓扑和化学修饰 mRNA。在这里，我们证明了优化的多尾 mRNA 在细胞转染后 24 到 72 小时内产生的发光信号比对照 mRNA 高出约 4.7-19.5 倍，14 天内可检测到的信号比对照 mRNA 高出约 4.7-19.5 倍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature biotechnology 工程技术-生物工程与应用微生物

CiteScore

63.00

自引率

1.70%

发文量

382

审稿时长

3 months

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