A TME-activated nano-catalyst for triple synergistic therapy of colorectal cancer

Colorectal cancer cells are highly heterogeneous and exhibit various drug resistances, making personalized treatment necessary. This typically involves a combination of different treatment modalities such as surgery, radiation, and chemotherapy to increase patient survival. Inspired by this, synergistic therapy, which combines multiple modalities into a single nanotherapeutic drug, shows promise in treating cancer. In this study, a nano-catalyst based on calcium peroxide (CaO 2 ) and the chemotherapeutic drug doxorubicin hydrochloride (DOX) co-loaded into HPB nanoparticles (HPB@CaO 2 /DOX-PAA) was developed to achieve synergistic cancer treatment through chemodynamic/chemo/photothermal (CDT/CT/PTT) mechanisms. After being endocytosed by cancer cells, the nano-catalyst decomposes, releasing cargo. During near-infrared light irradiation, HPB induces a photothermal effect, DOX exhibits significant RNA and DNA destruction capabilities, meanwhile CaO 2 produces a large amount of H 2 O 2 in the moderately acidic TME, which combines with Fe 2+ ions derived from HPB to form the highly toxic •OH in a Fenton-like reaction, enhancing the chemodynamic treatment. Assays conducted ex vivo and in vivo have exhibited the efficacy of this triple synergistic therapeutic regimen, indicating its potential clinical application.