siRNA-AGO2 complex inhibits bacterial gene translation: A promising therapeutic strategy for superbug infection

作者：Chen Wang, Wangjian Sheng, Yu Zhou, Xudong Hang, Jiayi Zhao, Yuanyuan Gu, Xiangfeng Meng, Yuefan Bai, Weili Li, Yujing Zhang, Linlin Zhang, Jing Yu, Zhen Zhou, Xiaona Li, Haorui Sun, Yanhong Xue, Tao Xu, Ke Zen, Hong Ling, Chenyu Zhang, Hongkai Bi, Huan Wang · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.101997 · 被引用次数：10 · 研究领域：RNA Interference and Gene Delivery、Advanced biosensing and bioanalysis techniques、Extracellular vesicles in disease

Silencing resistance genes of pathogenic bacteria by RNA interference (RNAi) is a potential strategy to fight antibiotic-resistant bacterial infections. Currently, RNAi cannot be achieved in bacteria due to the lack of RNA-induced silencing complex machinery and the difficulty of small interfering RNA (siRNA) delivery. Here, we show that exosomal siRNAs can be efficiently delivered into bacterial cells and can silence target genes primarily through translational repression without mRNA degradation. The exosomal Argonaute 2 (AGO2) protein forms a complex with siRNAs, which is essential for bacterial gene silencing. Both in vitro and in vivo-generated exosome-packaged siRNAs resensitize methicillin-resistant Staphylococcus aureus (MRSA) to methicillin treatment by silencing the mecA gene, which is the primary beta-lactam resistance determinant of MRSA. This approach significantly enhances the therapeutic effect in a mouse model of MRSA infection. In summary, our study provides a method for siRNA delivery to bacteria that may facilitate the treatment of antibiotic-resistant bacterial infection.