Copper-doped PDA nanoparticles with self-enhanced ROS generation for boosting photothermal/chemodynamic combination therapy

Chemodynamic therapy (CDT) kills tumor cells by converting intracellular hydrogen peroxide (H₂O₂) into cytotoxic hydroxyl radicals (˙OH) using metal ion-based agents via Fenton/Fenton-like reactions, exhibiting cancer specificity, excellent safety, and minimal side effects. However, the therapeutic effect of CDT is largely limited by high levels of the antioxidant glutathione (GSH) in cancer cells and low catalytic reaction rates of Fenton/Fenton-like reactions. Herein, folic acid (FA)-modified copper-doped polydopamine (PDA) nanoparticles were constructed to load curcumin (FPCCD), achieving the generation of self-enhanced reactive oxygen species (ROS) by inhibiting antioxidants and promoting the Fenton-like reaction. Briefly, FPCCD exhibited the following anticancer advantages: (1) FPCCD targeted tumor cells via FA receptor-mediated endocytosis for increased cellular uptake; (2) PDA-based photothermal therapy (PTT) elevated the catalytic reaction rate and ˙OH generation efficiency of CDT through hyperthermia; (3) copper doping not only enhanced the photothermal effect of PDA but also facilitated CDT through the Fenton-like reaction to deplete GSH and catalyze intracellular H₂O₂; and (4) the delivery of curcumin further depleted GSH to increase cytotoxic ˙OH, which promoted the thermal sensitivity of tumor cells and led to cell apoptosis. FPCCD exhibited efficient anti-tumor efficacy in C6 tumor-bearing mice, representing a potential strategy for enhancing CDT/PTT through self-enhanced ROS generation.