Vicious Cycle-Breaking Lipid Nanoparticles Remodeling Multi-Cellular Crosstalk to Reverse Liver Fibrosis.

During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs) and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches showed unsatisfactory efficacy and failed to meet clinical demand. Herein, a vicious cycle-breaking strategy was proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate modified and vismodegib loaded nanoparticles (CS-NPs/VDG) were designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid modified and silybin loaded nanoparticles (GA-NPs/SIB) were prepared to restore hepatocytes function by relieving oxidative stress. The results showed successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multi-regulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing anti-fibrotic regimens. This article is protected by copyright. All rights reserved.