Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis

Abstract

Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA–Lip–Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA–Lip–Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA–Lip–Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.