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

Nanomedicine (Lond). 2022 Aug;17(20):1411-1427. doi: 10.2217/nnm-2022-0083. Epub 2022 Nov 3.

Abstract

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.

Keywords: CRISPR/dCas9 system; HLCs; HSCs; exosomes; hepatic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Exosomes* / genetics
  • Hepatic Stellate Cells
  • Hepatocyte Nuclear Factor 3-beta
  • Hepatocytes
  • Humans
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / therapy
  • Retinol-Binding Proteins, Plasma

Substances

  • RBP4 protein, human
  • Retinol-Binding Proteins, Plasma
  • FOXA2 protein, human
  • Hepatocyte Nuclear Factor 3-beta