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Research Article

Targeted activation of HNF4α/HGF1/FOXA2 reverses hepatic fibrosis via exosome-mediated delivery of CRISPR/dCas9-SAM system

    Nianan Luo‡

    Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China

    Department of General Surgery, 943 Hospital of PLA, Wuwei, 733000, China

    ‡These authors contributed equally to this work

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    ,
    Wenjun Zhong‡

    Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China

    School of Clinical Medicine, Xi'an Medical University, Xi'an, 710032, China

    ‡These authors contributed equally to this work

    Search for more papers by this author

    ,
    Jiangbin Li

    Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China

    ,
    Zhongjie Zhai

    Department of Military Preventive Medicine, Fourth Military Medical University, Xi'an, 710032, China

    ,
    Jianguo Lu

    *Author for correspondence:

    E-mail Address: lujguo@yeah.net

    Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China

    &
    Rui Dong

    **Author for correspondence:

    E-mail Address: dongrui2020@yeah.net

    Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China

    Published Online:https://doi.org/10.2217/nnm-2022-0083

    Aim: Hepatic fibrosis is one of the most common conditions worldwide, and yet no effective antifibrotic therapy is available. This study aimed to reverse hepatic fibrosis via exosome-mediated delivery of the CRISPR/dCas9-SAM system. Materials & methods: The authors constructed a modified-exosome delivery system targeting hepatic stellate cells (HSCs), and constructed the CRISPR/dCas9-SAM system inducing HSCs convert into hepatocyte-like cells in vitro and in vivo. Results: RBP4-modified exosomes could efficiently load and deliver the CRISPR/dCas9 system to HSCs. The in vitro CRISPR/dCas9 system induced the conversion from HSCs to hepatocyte-like cells via targeted activation of HNF4α/HGF1/FOXA2 genes. Importantly, in vivo targeted delivery of this system significantly attenuated CCl4-induced hepatic fibrosis. Conclusion: Targeted activation of HNF4α/HGF1/FOXA2 reverses hepatic fibrosis via exosome-mediated delivery of the CRISPR/dCas9-SAM system, which provides a feasible antifibrotic strategy.

    Graphical abstract

    References

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