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

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

in 631/337/1645/2570 / 631/45/500 / 631/61/201 / 631/61/391 / 631/92/500 / Agriculture / Animals / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Coronaviruses / COVID-19 / Efficiency / Gene Editing / Gene expression / Humans / Life Sciences / Liver - metabolism / Mice / mRNA / mRNA vaccines / Poly A - chemistry / Poly A - genetics / Polyadenine / Proprotein Convertase 9 - genetics / Protein Biosynthesis - genetics / Protein folding / Proteins / Ribonucleic acid / RNA / RNA, Messenger - chemistry / RNA, Messenger - genetics / RNA, Messenger - metabolism / Synthesis / Transfection / Translation / Variance analysis

2025

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2025

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2025

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Journal Article

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

Aditham, Abhishek,

Guo, Jianting,

Wu, Mingrui,

Liu, David R.,

Ren, Jingyi,

Liu, Dangliang,

Chen, Hongyu,

Hsu, Alvin,

Tian, Jiakun,

Luo, Shuchen,

Huang, Jiahao,

Zhou, Yiming,

Kostas, Franklin,

Wang, Xiao

2025

Overview

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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Publisher

Nature Publishing Group US,Nature Publishing Group

Subject

/ Animals