Targeted Activation of <i>HNF4α/HGF1/FOXA2</i> Reverses Hepatic Fibrosis Via Exosome-Mediated Delivery of CRISPR/dCas9-SAM System

Abstract

<b>Aim:</b> 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. <b>Materials & methods:</b> 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 <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> RBP4-modified exosomes could efficiently load and deliver the CRISPR/dCas9 system to HSCs. The <i>in vitro</i> CRISPR/dCas9 system induced the conversion from HSCs to hepatocyte-like cells via targeted activation of <i>HNF4α</i>/<i>HGF1</i>/<i>FOXA2</i> genes. Importantly, <i>in vivo</i> targeted delivery of this system significantly attenuated CCl₄-induced hepatic fibrosis. <b>Conclusion:</b> Targeted activation of <i>HNF4α</i>/<i>HGF1</i>/<i>FOXA2</i> reverses hepatic fibrosis via exosome-mediated delivery of the CRISPR/dCas9-SAM system, which provides a feasible antifibrotic strategy.