Hyaluronic acid modified extracellular vesicles targeting hepatic stellate cells to attenuate hepatic fibrosis

Rationale: Transforming growth factor-beta1 (TGF-beta 1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-beta 1 signaling pathway to alleviate hepatic stellate cells (HSC) activation mediated hepatic fibrosis. The targeting delivery strategy of PFD to hepatic stellate cells is a challenge. Extracellular vesicles (EVs), cell-derived membranous particles are intraluminal nano-vesicles that play a vital role in intercellular communication, they also be considered as an ideal nano-carrier. Methods: In this study, we developed a target strategy to deliver PFD to HSC with CD44 over-expression by EVs, hyaluronic acid (HA) modified DSPE-PEG2000 endows the active targeting ability of activated HSCs to PFDloaded EVs. Results: In both rat hepatic stellate cell line HSC-T6 and rat hepatocyte cell line BRL, HA@EVs-PFD demonstrated the capacity to down-regulate the expression of collagen-synthesis-related proteins and showed superior inhibition efficacy of HSC-T6 activation compared to free PFD. In hepatic fibrosis model, 4 weeks of HA@EVs-PFD treatment resulted in a reduction in liver collagen fibers, significant improvement in hepatic cell morphology, and amelioration of hepatic fibrosis. Conclusions: HA@EVs-PFD, as a drug delivery system that effectively targets and inhibits activated HSCs to treat hepatic fibrosis, holds promise as a potential therapeutic agent against hepatic fibrosis.