Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme‐Loaded Electrophilic ZIFs

Redox homeostasis is one of the main reasons for reactive oxygen species (ROS) tolerance in hypoxic tumors, limiting ROS‐mediated tumor therapy. Proposed herein is a redox dyshomeostasis (RDH) strategy based on a nanoplatform, FeCysPW@ZIF‐82@CAT Dz, to disrupt redox homeostasis, and its application to improve ROS‐mediated hypoxic tumor therapy. Once endocytosed by tumor cells, the catalase DNAzyme (CAT Dz) loaded zeolitic imidazole framework‐82 (ZIF‐82@CAT Dz) shell can be degraded into Zn 2+ as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione (GSH) depletion under hypoxia, both of which lead to intracellular RDH and H 2 O 2 accumulation. These “disordered” cells show reduced resistance to ROS and are effectively killed by ferrous cysteine‐phosphotungstate (FeCysPW) induced chemodynamic therapy (CDT). In vitro and in vivo data demonstrate that the pH/hypoxia/H 2 O 2 triple stimuli responsive nanocomposite can efficiently kill hypoxic tumors. Overall, the RDH strategy provides a new way of thinking about ROS‐mediated treatment of hypoxic tumors.