Targeted delivery of polymeric NO-donor micelles to hepatic stellate cells for restoration of liver function and inhibition of hepatic fibrosis

Liver fibrosis is a prevalent liver disease associated with significant morbidity, and the activation of hepatic stellate cells (HSCs) serves as the primary causative factor driving the progression of liver fibrosis. However, capillarization of liver sinusoidal endothelial cells (LSECs) induced by hepatic fibrosis can reduce nitric oxide (NO) production and bioavailability, which consequently loses the ability to retain HSCs dormant, leading to amplified HSCs activation. Herein, an elaborate micelle (VN-M@BN) loaded with benazepril (BN) was constructed by self-assembly of polymeric NO donor, aiming for the controlled release of NO in liver fibrosis lesions thereby impeding the progression of liver fibrosis. VN-M@BN with the vitamin A (VA) ligand modification was designed to target HSCs for efficient liver fibrosis inhibition. Controlled NO release significantly downregulated α-smooth muscle actin (α-SMA) and induced apoptosis of activated HSCs, thus enhancing the inhibition effects of BN towards HSCs. Furthermore, the in suit antifibrotic treatment results confirmed that VN-M@BN possessed good circulatory stability and targetability to liver fibrotic tissues, thereby effectively ameliorating the collagen deposition and fibrosis process in damaged liver tissues. The NO-based targeted nanodrug system enabled precise delivery of therapeutic drugs to activated HSCs, thereby synergizing the efficacy in treating liver fibrosis with minimal adverse effects.