A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia

The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H₂O₂ enriched in tumor tissues to O₂. Nonetheless, the catalase activity may not be optimal at body temperature and the O₂ supply may not meet the rapid O₂ consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O₂ production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O₂ to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.