Volume 31, No 6, Jun 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 6, June 2021: 631-648   |  Open Access

ORIGINAL ARTICLES

In vivo self-assembled small RNAs as a new generation of RNAi therapeutics

Zheng Fu^1,2,3 , Xiang Zhang¹ , Xinyan Zhou¹ , Uzair Ur-Rehman¹ , Mengchao Yu^1,4 , Hongwei Liang¹ , Hongyuan Guo¹ , Xu Guo¹ , Yan Kong¹ , Yuanyuan Su¹ , Yangyang Ye¹ , Xiuting Hu¹ , Wei Cheng⁵ , Jinrong Wu⁶ , Yanbo Wang¹ , Yayun Gu³ , Sheng-feng Lu⁷ , Dianqing Wu⁸ , Ke Zen¹ , Jing Li^1,* , Chao Yan^1,2,3,* , Chen-Yu Zhang^1,* , Xi Chen^1,2,3,*

¹Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), Institute of Artificial Intelligence Biomedicine, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
²Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, Jiangsu, China
³State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
⁴Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
⁵Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
⁶Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China
⁷Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
⁸Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT, USA
These authors contributed equally: Zheng Fu, Xiang Zhang, Xinyan Zhou, Uzair Ur-Rehman, Mengchao Yu Correspondence: Jing Li(jingli220@nju.edu.cn)Chao Yan(yanchao@nju.edu.cn)Chen-Yu Zhang(cyzhang@nju.edu.cn)Xi Chen(xichen@nju.edu.cn)

RNAi therapy has undergone two stages of development, direct injection of synthetic siRNAs and delivery with artificial vehicles or conjugated ligands; both have not solved the problem of efficient in vivo siRNA delivery. Here, we present a proof-of-principle strategy that reprogrammes host liver with genetic circuits to direct the synthesis and self-assembly of siRNAs into secretory exosomes and facilitate the in vivo delivery of siRNAs through circulating exosomes. By combination of different genetic circuit modules, in vivo assembled siRNAs are systematically distributed to multiple tissues or targeted to specific tissues (e.g., brain), inducing potent target gene silencing in these tissues. The therapeutic value of our strategy is demonstrated by programmed silencing of critical targets associated with various diseases, including EGFR/KRAS in lung cancer, EGFR/TNC in glioblastoma and PTP1B in obesity. Overall, our strategy represents a next generation RNAi therapeutics, which makes RNAi therapy feasible.

https://doi.org/10.1038/s41422-021-00491-z

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