2. Academic Validation
  3. In vivo self-assembled small RNAs as a new generation of RNAi therapeutics

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

  • Cell Res. 2021 Jun;31(6):631-648. doi: 10.1038/s41422-021-00491-z.
Zheng Fu  # 1 2 3,  Xiang Zhang  # 1,  Xinyan Zhou  # 1,  Uzair Ur-Rehman  # 1,  Mengchao Yu  # 1 4,  Hongwei Liang 1,  Hongyuan Guo 1,  Xu Guo 1,  Yan Kong 1,  Yuanyuan Su 1,  Yangyang Ye 1,  Xiuting Hu 1,  Wei Cheng 5,  Jinrong Wu 6,  Yanbo Wang 1,  Yayun Gu 3,  Sheng-Feng Lu 7,  Dianqing Wu 8,  Ke Zen 1,  Jing Li 9,  Chao Yan 10 11 12,  Chen-Yu Zhang 13,  Xi Chen 14 15 16
Affiliations

Affiliations

  • 1 Nanjing 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.
  • 2 Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
  • 5 Department of General Surgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 6 Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
  • 7 Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 8 Department of Pharmacology, Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT, USA.
  • 9 Nanjing 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. [email protected].
  • 10 Nanjing 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. [email protected].
  • 11 Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • 12 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • 13 Nanjing 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. [email protected].
  • 14 Nanjing 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. [email protected].
  • 15 Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • 16 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 33782530 DOI: 10.1038/s41422-021-00491-z
Abstract

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.

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