Natural polysaccharide-based smart CXCR4-targeted nano-system for magnified liver fibrosis therapy

Activated hepatic stellate cells (aHSCs), the main source of extracellular matrix deposition, are key targets in liver fibrosis. However, no effective drug specific to aHSCs has been clinically applied due to poor drug delivery efficiency. Herein, we designed a CXC chemokine receptor 4 (CXCR4)-targeted reactive oxygen species (ROS)-responsive platform AMD-Dex-ROS-responsive-sorafenib (ARS) based on natural polysac-charide and thioctic acid frame, which can deliver anti-fibrosis drug represented by sorafenib specifically to aHSCs on account of CXCR4 over-expression on aHSCs, and smartly disassemble via ROS-responsive thioketal rupture relying on high intracellular ROS in HSCs, realized on-demand drug release and effec-tive liver fibrosis reversion. Notably, in this platform, the CXCR4 antagonist AMD3100 not only enhanced aHSCs targeting efficiency of sorafenib but also effectively magnified the aHSCs elimination of sorafenib by blocking stroma cell derived factor-1 (SDF-1)/CXCR4-induced aHSCs protection, resulting in synergis-tic anti-fibrosis effect. The platform provided a new approach for drug delivery system design and liver fibrosis treatment.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

The study designed a drug delivery system that can specifically deliver anti-fibrosis drugs to activated hepatic stellate cells and achieve on-demand drug release and effective fibrosis reversion. It was found that the addition of a CXCR4 antagonist in the system enhanced the targeting efficiency of the drug and resulted in synergistic anti-fibrosis effect.