Construction of hepatic stellate cells-targeted nanosystem of verteporfin for the effective treatment of liver fibrosis through mechanical signal modulation

Abstract The mechanical traction caused by high cross-linking extracellular matrix (ECM) can promote the continuous activation of hepatic stellate cells (HSCs) by yes-associated protein (YAP)-mediated mechanical signal. Therefore, targeted inhibiting the activation of HSCs induced by mechanical traction is the main measure to improve liver fibrosis. The activated HSCs (aHSCs)-targeted drug delivery nanosystem of verteporfin@polyethyleneimine-vitamin A (VP@PSA), which loaded VP a small molecule inhibitor of YAP in the Hippo signaling pathway to regulate mechanical signal transduction was constructed. The particle size of VP@PSA was 167.1 ± 1.5 nm with great stability, and the drug loading of VP was 34.39 ± 2.41% and encapsulation efficiency was 93.28 ± 1.57%. The targeting and therapeutic effect of VP@PSA were verified by immunofluorescence, flow cytometry and competitive inhibition experiments. The biocompatibility was evaluated by hemolysis, pyrogen, vascular stimulation, respiration and behavior. Compared with non-targeted delivery system, VP@PSA showed best targeting ability to aHSCs among different kinds of liver cells. VP@PSA had an excellent therapeutic effect on suppressing the activation of HSCs, reducing ECM deposition and improving liver fibrosis by regulating YAP/ lysyl oxidase like 2/connective tissue growth factor signal in vitro and in vivo . Furthermore, VP@PSA had favorable biological safety and no toxicity to the main organs. The constructed VP@PSA delivery system laid a solid theoretical and experimental foundation for developing clinical targeted drugs for liver fibrosis.