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.

尽管信使 RNA (mRNA) 已被证明作为疫苗是有效的，但其作为一般治疗方式的潜力因其不稳定性和低翻译能力而受到限制。为了增加 mRNA 蛋白质表达的持续时间和水平，我们设计并合成了具有多个合成 Poly(A) 尾的拓扑和化学修饰的 mRNA。在这里，我们证明，在细胞中转染后 24 至 72 小时，优化的多尾 mRNA 产生的发光信号比对照 mRNA 高约 4.7–19.5 倍，并且与体内对照的信号相比，14 天可检测到信号小于 7 天。我们进一步以最小的 mRNA 剂量实现了小鼠肝脏中临床相关基因Pcsk9和Angptl3的高效多重基因组编辑。总而言之，这些结果提供了一种合成带帽分支 mRNA 的通用方法，其翻译能力显着增强。