Advances of Covalent Chemical Modifications of RNA

Chemical modification of RNA can endow RNA molecules with novel structures and functions, enabling broader clinical application potential. RNA chemical modification is a systematic and controllable engineering approach, particularly at the cellular or tissue level, requiring precise modification strategies to reduce off-target effects and enhance spatiotemporal controllability. Although enzyme-and light-mediated chemical modifications are widely employed for RNA engineering, these strategies are hindered by the complex enzymatic environment within cells and the low light penetration. This review summarizes the field of chemical RNA modifications using diverse approaches, including enzyme, light, and synthetic reactions mediated strategies, such as nucleotide incorporation, light-induced RNA silencing, bioorthogonal RNA modification, post-transcriptional modification, and deprotection. By introducing the advantages and disadvantages of various RNA modification strategies, this review provides a reference for designing and developing novel RNA modification to achieve efficient, precise, and spatiotemporally specific RNA modification strategies.