siRNA-AGO2 complex inhibits bacterial gene translation: A promising therapeutic strategy for superbug infection
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.
Authors
- Hong Ling (ORCID: https://orcid.org/0000-0002-1886-1242)
- Hongkai Bi
- Yuefan Bai (ORCID: https://orcid.org/0009-0005-9793-1665)
- Yanhong Xue (ORCID: https://orcid.org/0000-0003-3214-4175)
- Jing Yu (ORCID: https://orcid.org/0000-0002-5263-3032)
- Jiayi Zhao (ORCID: https://orcid.org/0000-0001-9975-9911)
- Xiangfeng Meng (ORCID: https://orcid.org/0000-0002-7358-505X)
- Xudong Hang
- Zhen Zhou (ORCID: https://orcid.org/0000-0003-0706-9089)
- Yu Zhou (ORCID: https://orcid.org/0009-0006-4284-8845)
- Ke Zen (ORCID: https://orcid.org/0000-0002-5166-2974)
- Yujing Zhang (ORCID: https://orcid.org/0000-0002-8265-2488)
- Huan Wang (ORCID: https://orcid.org/0000-0003-0126-4983)
- Chen Wang (ORCID: https://orcid.org/0000-0001-6461-1271)
- Chenyu Zhang (ORCID: https://orcid.org/0000-0002-6739-4724)
- Weili Li (ORCID: https://orcid.org/0000-0001-8999-8775)
- Linlin Zhang (ORCID: https://orcid.org/0000-0002-0823-7825)
- Xiaona Li (ORCID: https://orcid.org/0000-0001-9472-4912)
- Tao Xu (ORCID: https://orcid.org/0000-0001-7395-0451)
- Yuanyuan Gu (ORCID: https://orcid.org/0009-0005-4018-0338)
- Haorui Sun (ORCID: https://orcid.org/0000-0001-9807-5411)
- Wangjian Sheng
Institutions
- Jiangsu University (CN)
- Harbin Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nanjing Drum Tower Hospital (CN)
- Institute of Biophysics (CN)
- Hainan Medical University (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101997
- Citations
- 8
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province
- Senior Talent Foundation of Jiangsu University
- Fundamental Research Funds for the Central Universities