Metal-phenolic nanoparticles with ROS/pH dual-responsiveness for liver fibrosis therapy via synergistic microenvironment remodeling and metabolic reprogramming.

Liver fibrosis represents the common pathological outcome of diverse chronic liver diseases. Without timely intervention, it may progress into life-threatening cirrhosis or liver cancer. The imbalance of the microenvironment caused by oxidative stress and inflammation is a key driver of hepatic stellate cells (HSCs) activation in liver fibrosis. Moreover, the glycolytic pathway on which activated HSCs depend for proliferation also represents an important therapeutic target. Therefore, this study designed a reactive oxygen species (ROS)/pH dual-responsive nanosystem (CPT@EZ@HP) possessing potent antioxidant and anti-inflammatory activities, aiming to synergistically remodel the microenvironment and reprogram metabolism for liver fibrosis therapy. The nanosystem utilized Zn2 + -epigallocatechin gallate (EGCG) metal-phenolic coordination to encapsulate camptothecin (CPT), followed by surface modification with phenylboronic acid-conjugated hyaluronic acid to impart CD44-targeting and ROS-responsive properties. In liver fibrosis, CPT@EZ@HP targets activated HSCs with high CD44 expression. Subsequently, the boronic ester bonds on its surface undergo cleavage in the ROS microenvironment, exposing the internal CPT@EZ. This structure remodels the liver microenvironment by scavenging ROS and promoting macrophage polarization toward the M2 phenotype, thereby inhibiting HSCs activation. Furthermore, acidic conditions induce pH-responsive dissociation in CPT@EZ, accelerating the release of CPT. Notably, the released CPT reduces energy supply by inhibiting HIF-1α-mediated glycolysis, thereby effectively suppressing the proliferation of activated HSCs. In vivo assessment confirmed that CPT@EZ@HP markedly attenuated liver fibrosis, reduced collagen deposition, and improved liver function-related indicators. This study proposes a novel therapeutic strategy against liver fibrosis, achieved through the synergistic integration of targeted delivery, microenvironment remodeling, and metabolic reprogramming.