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In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis

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  • Xinyan Zhou

    (Nanjing University)

  • Mengchao Yu

    (Qingdao Municipal Hospital, Qingdao University)

  • Luzhen Ma

    (Nanjing University)

  • Jinyu Fu

    (Nanjing University)

  • Jingwei Guo

    (Nanjing University)

  • Jieqiong Lei

    (Nanjing University)

  • Zheng Fu

    (Nanjing University
    Nanjing University)

  • Yong Fu

    (Nanjing University)

  • Qipeng Zhang

    (Nanjing University)

  • Chen-Yu Zhang

    (Nanjing University
    Chinese Academy of Medical Sciences
    Nanjing University
    Shenzhen Bay Laboratory)

  • Xi Chen

    (Nanjing University
    Nanjing University
    Nanjing University
    Shenzhen Bay Laboratory)

Abstract

Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.

Suggested Citation

  • Xinyan Zhou & Mengchao Yu & Luzhen Ma & Jinyu Fu & Jingwei Guo & Jieqiong Lei & Zheng Fu & Yong Fu & Qipeng Zhang & Chen-Yu Zhang & Xi Chen, 2022. "In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33436-0
    DOI: 10.1038/s41467-022-33436-0
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    References listed on IDEAS

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    1. Ruben Garcia-Martin & Guoxiao Wang & Bruna B. Brandão & Tamires M. Zanotto & Samah Shah & Sandip Kumar Patel & Birgit Schilling & C. Ronald Kahn, 2022. "MicroRNA sequence codes for small extracellular vesicle release and cellular retention," Nature, Nature, vol. 601(7893), pages 446-451, January.
    2. Linkang Zhou & Shi-Young Park & Li Xu & Xiayu Xia & Jing Ye & Lu Su & Kyeong-Hoon Jeong & Jang Ho Hur & Hyunhee Oh & Yoshikazu Tamori & Cristina M. Zingaretti & Saverio Cinti & Jesús Argente & Miao Yu, 2015. "Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
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