Ablation of Gap Junction Protein Improves the Efficiency of Nanozyme‐Mediated Catalytic/Starvation/Mild‐Temperature Photothermal Therapy

Abstract Reactive oxygen species (ROS)‐mediated tumor catalytic therapy is typically hindered by gap junction proteins that form cell‐to‐cell channels to remove cytotoxic ROS, thereby protecting tumor cells from oxidative damage. In this work, a multifunctional nanozyme, FePGOGA, is designed and prepared by Fe(III)‐mediated oxidative polymerization (FeP), followed by glucose oxidase (GOx) and GAP19 peptides co‐loading through electrostatic and π–π interactions. The FePGOGA nanozyme exhibits excellent cascade peroxidase‐ and glutathione‐oxidase‐like activities that efficiently catalyze hydrogen peroxide conversion to hydroxyl radicals and convert reduced glutathione to oxidized glutathione disulfide. The loaded GOx starves the tumors and aggravates tumor oxidative stress through glucose decomposition, while GAP19 peptides block the hemichannels by inducing degradation of Cx43, thus increasing the accumulation of intracellular ROS, and decreasing the transport of intracellular glucose. Furthermore, the ROS reacts with primary amines of heat shock proteins to destroy their structure and function, enabling tumor photothermal therapy at the widely sought‐after mild temperature (mildPTT, ≤45 °C). In vivo experiments demonstrate the significant antitumor effectof FePGOGA on cal27 xenograft tumors under near‐infrared light irradiation. This study demonstrates the successful ablation of gap junction proteins to overcome resistance to ROS‐mediated therapy, providing a regulator to suppress tumor self‐preservation during tumor starvation, catalytic therapy, and mildPTT.