One-pot microwave-derived copper-doped red-emissive carbon dots with multienzyme activities for synergistic CDT/PDT enhancement via glutathione depletion

Cancer remains a leading cause of global mortality, with nearly 10 million annual deaths. High intracellular glutathione (GSH) levels and tumor hypoxia critically limit chemotherapy efficacy and photodynamic therapy (PDT) effectiveness. Conventional nanocatalytic materials, particularly blue/green-emitting nanomaterials, face limited deep-tissue penetration, hindering their utility in bioimaging and targeted therapy. Herein, we report a microwave-assisted one-pot synthesis of copper-doped red-emissive carbon dots (Cu-CDs) using dicyandiamide, 4′-aminoacetanilide, and anhydrous copper sulfate as precursors. The synthesized Cu-CDs exhibit excellent optical properties ( λ ex / λ em  = 525/595 nm) with a quantum yield of 12.7%, enabling nuclear fluorescent imaging for precise tumor localization. Notably, Cu-CDs demonstrate triple-enzyme (peroxidase, catalase, oxidase) mimetic activities, which synergistically deplete GSH, alleviate tumor hypoxia, and enhance reactive oxygen species (ROS) generation. In vitro studies revealed that Cu-CDs-mediated chemodynamic therapy (CDT) alone achieved 60.4% tumor cell apoptosis, while combination with PDT elevated the rate to 92.96%. Mechanistically, Cu-CDs exploit endogenous H 2 O 2 overexpression in tumors to produce cytotoxic ‧OH radicals via peroxidase activity, while catalase activity mitigates hypoxia by decomposing H 2 O 2 into O 2 . This multi-enzyme synergy reduces ROS scavenging by GSH, amplifying PDT efficacy. Biocompatibility assessments confirmed low cytotoxicity and efficient cellular uptake of Cu-CDs. The red-emissive feature enables deep-tissue penetration and nuclear targeting, minimizing off-target damage. This work establishes a paradigm for metal-doped CDs in cancer theranostics, overcoming single-enzyme limitations and advancing synergistic enzyme-mimetic therapy. The strategy holds significant promise for biomedical applications, offering a novel platform for precision tumor treatment.