Polyoxometalate-Containing Nanocomposite Hydrogels for Cascade-Catalytic and Photothermal Dually Enhanced Chemodynamic Therapy

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species (ROS)-mediated cancer therapies. However, the lack of endogenous hydrogen peroxide (H₂O₂) in tumors and the low catalytic efficiency of traditional Fenton catalysts limit the therapeutic effect of CDT. Herein, an injectable nanocomposite hydrogel (HA-DOPA/W-POM/1-S-S-PEG@GOx) based on the hyaluronic acid-dopamine (HA-DOPA) matrix is designed to deliver tungsten-based polyoxometalates (W-POM) and peptide nanomicelles (1-S-S-PEG@GOx) for achieving cascade-catalytic and photothermal dually enhanced CDT. Upon tumor cell uptake, 1-S-S-PEG@GOx specifically responds to endogenous glutathione and disassembles to release glucose oxidase (GOx), which catalyzes the oxidation of glucose to produce H₂O₂. On the one hand, W-POM functions as peroxidase-like nanozymes to convert H₂O₂ into a hydroxyl radical (^·OH) under the aid of GOx, enhancing the efficacy of CDT through cascade-catalytic reactions (i.e., glucose to H₂O₂ to ^·OH). On the other hand, W-POM acts as a photothermal therapy agent, generating mild heat under near-infrared laser irradiation to achieve photothermal-enhanced CDT. This cascade-catalytic and photothermal dually enhanced CDT triggers an intracellular ROS storm, leading to apoptosis and ferroptosis of tumor cells. Importantly, in situ administration of HA-DOPA/W-POM/1-S-S-PEG@GOx alongside laser irradiation showcases enhanced antitumor efficacy and satisfactory biocompatibility in vivo, which holds great potential for the development of functional nanomedicine toward targeted tumor therapy.