Tumor acidity-activatable photothermal/Fenton nanoagent for synergistic therapy

Intracellular formation of therapeutic agents has become one of the effective ways for cancer-specific treatment. Herein, a tumor acidity-activatable photothermal/Fenton nanoagent (denoted as CoPy) was constructed based on oxidized zeolitic imidazolate framework-67 (oxZIF-67) nanosheet and pyrrole (Py) monomer for synergistic therapy. The CoPy showed negligible toxicity to normal cell models RAW264.7 and 3T3 cell lines, and could be degraded by ascorbic acid in normal physiological conditions. However, once uptaken by 4T1 cells, the acidic pH led to the release of Co³⁺, which served as a strong oxidant to induce the polymerization of Py to form polypyrrole (PPy) for site-specific photothermal therapy (PTT). Most appealingly, the PPy could chelate the generated Co²⁺ in the polymerization process to initiate the Fenton-like reaction, which was more capable to produce highly toxic hydroxyl radical (•OH) for chemodynamic therapy (CDT) compared to the free Co²⁺ ones. In vitro and in vivo experiments demonstrated that all functionalities on CoPy worked collaboratively, and 78% of tumors were inhibited through cooperative PTT/CDT. Such a novel therapeutic nanoagent with tumor selectivity opens new opportunities for combinational treatment paradigms.