Photothermal-enhanced ROS storm by hyaluronic acid-conjugated nanocatalysts to amplify tumor-specific photo-chemodynamic therapy and immune response.

Integrating photodynamic therapy (PDT) and chemodynamic therapy (CDT) shows promising potential in tumor treatment. Nevertheless, the lack of specific tumor targeting, serious photobleaching, and poor photothermal effect of photosensitizers, the intracellular low Fenton reaction efficiency, and glutathione (GSH)-elicited reactive oxygen species (ROS) depletion profoundly restrict ROS-mediated cancer therapy. To enhance ROS generation with the assistance of photothermal therapy (PTT), the hyaluronic acid (HA)-decorated Fe-MIL-88B (MIL) nanocatalysts were fabricated for tumor-targeted delivery of photosensitizer IR820. The IR820@HA-coated MIL (IHM) nanocatalysts remarkably enhanced the photothermal conversion efficacy and singlet oxygen (1O2) production of IR820 and lowered IR820 photobleaching. The IHM nanocatalysts promoted the conversion of H2O2 into toxic ·OH upon thermo/acidity-enhanced Fe3+-mediated Fenton reaction and consumed GSH via Fe3+-elicited GSH oxidation. After being internalized by 4 T1 cancer cells via CD44-mediated endocytosis, the IHM nanocatalysts under irradiation of near-infrared (NIR) laser prominently produced hyperthermia and strong ROS storm, thereby causing apoptosis and ferroptosis via mitochondria damage and lipid peroxidation, and inducing immunogenic cell death (ICD). Through HA-mediated tumor targeting, the IHM nanocatalysts effectively accumulated in 4 T1 tumor and inhibited tumor growth and lung metastasis by PTT-enhanced PDT/CDT combined with ferroptosis and ICD-amplified antitumor immune response, showing great promise in future tumor treatment.