Redox-Responsive Thioketal-Crosslinked Gelatin Hydrogels for Tumor Microenvironment–Triggered Drug Release in Liver Cancer

Background: The liver tumor microenvironment is characterized by elevated reactive oxygen species (ROS), high glutathione (GSH) levels, and acidic pH, which limits the selectivity and efficacy of conventional chemotherapy. Microenvironment-responsive drug delivery systems offer a promising strategy to address these challenges. Methods: A redox-responsive thioketal-crosslinked gelatin hydrogel (TK-Gel) was prepared via dynamic covalent crosslinking and used to encapsulate doxorubicin (DOX). The rheological properties, swelling and degradation behaviors, redox responsiveness, and microenvironment-dependent drug release were systematically evaluated. In vitro antitumor performance was assessed using HepG2 liver cancer cells. Results: The TK-Gel hydrogel formed a stable and highly hydrated network under physiological conditions, while exhibiting accelerated degradation and enhanced DOX release under tumor-mimicking environments with elevated ROS and GSH. Cellular studies demonstrated good biocompatibility of the blank hydrogel and significantly enhanced cytotoxicity of DOX@TK-Gel under redox-activated conditions, accompanied by partial intracellular ROS consumption. Conclusions: Thioketal-crosslinked gelatin hydrogels enable tumor-selective drug release and redox modulation, providing a promising platform for liver cancer therapy.