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 (HO) 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/-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 (-S-S-PEG@GOx) for achieving cascade-catalytic and photothermal dually enhanced CDT. Upon tumor cell uptake, -S-S-PEG@GOx specifically responds to endogenous glutathione and disassembles to release glucose oxidase (GOx), which catalyzes the oxidation of glucose to produce HO. On the one hand, W-POM functions as peroxidase-like nanozymes to convert HO into a hydroxyl radical (OH) under the aid of GOx, enhancing the efficacy of CDT through cascade-catalytic reactions (i.e., glucose to HO 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/-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.