美国麻省理工学院Xiao Wang小组发现，化学和拓扑设计的多加帽mRNA和加帽环状RNA可增强翻译效率。相关论文于2024年9月23日在线发表在《自然—生物技术》杂志上。

研究人员报告了一种名为连接增强mRNA-寡核苷酸组装（LEGO）的方法来增强翻译。研究人员系统筛选了不同的化学拓扑特征，发现支链mRNA帽有效启动线性或环状mRNA的翻译，无需内部核糖体进入位点。两种化学修饰，分别是帽上的锁核酸（LNA）N⁷-甲基鸟苷修饰和5'非翻译区的LNA + 5 × 2' O-甲基修饰，增强了RNA与真核翻译起始因子（eIF4E–eIF4G）的结合及RNA在体外抵抗去帽的稳定性。

通过对双加帽mRNA和加帽环状RNA的多维化学拓扑工程，研究人员在体内提高了mRNA蛋白生产量多达十倍，导致在严重急性呼吸综合症冠状病毒2号疫苗接种后，抗体生产量分别提高了17倍和3.7倍。LEGO平台为设计超越经典线性和环状RNA的非天然RNA结构和拓扑开辟了可能性，适用于基础研究和治疗应用。

研究人员表示，基于mRNA的蛋白质和疫苗疗法将受益于翻译能力的提高。

附：英文原文

Title: Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation

Author: Chen, Hongyu, Liu, Dangliang, Aditham, Abhishek, Guo, Jianting, Huang, Jiahao, Kostas, Franklin, Maher, Kamal, Friedrich, Mirco J., Xavier, Ramnik J., Zhang, Feng, Wang, Xiao

Issue&Volume: 2024-09-23

Abstract: Protein and vaccine therapies based on mRNA would benefit from an increase in translation capacity. Here, we report a method to augment translation named ligation-enabled mRNA–oligonucleotide assembly (LEGO). We systematically screen different chemotopological motifs and find that a branched mRNA cap effectively initiates translation on linear or circular mRNAs without internal ribosome entry sites. Two types of chemical modification, locked nucleic acid (LNA) N7-methylguanosine modifications on the cap and LNA+5×2′ O-methyl on the 5′ untranslated region, enhance RNA–eukaryotic translation initiation factor (eIF4E–eIF4G) binding and RNA stability against decapping in vitro. Through multidimensional chemotopological engineering of dual-capped mRNA and capped circular RNA, we enhanced mRNA protein production by up to tenfold in vivo, resulting in 17-fold and 3.7-fold higher antibody production after prime and boost doses in a severe acute respiratory syndrome coronavirus 2 vaccine setting, respectively. The LEGO platform opens possibilities to design unnatural RNA structures and topologies beyond canonical linear and circular RNAs for both basic research and therapeutic applications.

DOI: 10.1038/s41587-024-02393-y

Source: https://www.nature.com/articles/s41587-024-02393-y