Photothermal-Augmented Cascade Catalysis: Engineering Nanozymes for Tumor ROS Burst Therapy

Nanozyme-based catalytic therapy triggered by tumor-specific endogenous stimuli is an emerging tumor therapy that has attracted significant attention. Nevertheless, the efficacy of current catalytic therapies is severely limited by the intrinsic catalytic efficiency of nanozymes and the low concentration of endogenous substrates. Herein, a novel and efficient CuS-COF@PDA/Apt-A/GOx (Cu-CPAG) nanozyme was rationally designed with multiple enzyme-like catalytic activities and an augmented photothermal effect. Meanwhile, the nanozyme could ingeniously bind to the overexpressed MUC1 protein in MCF-7 cells, thus effectively addressing the critical limitations of conventional catalytic therapy. Following targeted internalization, glucose oxidase (GOx) within the nanozyme catalyzes the oxidation of glucose to elevate endogenous hydrogen peroxide (H₂O₂) levels in tumor cells and trigger a cellular starvation effect. Then, the accumulated H₂O₂ is subsequently converted by CuS NPs into highly cytotoxic hydroxyl radicals (^•OH), which significantly promotes the intracellular accumulation of reactive oxygen species (ROS) in a cascade manner. Notably, owing to the excellent photothermal properties of CuS NPs and polydopamine (PDA), near-infrared laser irradiation exerts a distinct photothermal-augmented effect to further enhance the overall catalytic efficiency of the nanozyme, thereby inducing an amplified ROS burst in tumor cells. Consequently, the designed Cu-CPAG nanozyme can disrupt redox homeostasis in the tumor region through a photothermal-augmented cascade reaction, effectively overcoming the shortcomings of traditional nanozyme catalytic therapy. This work develops a promising strategy for cascade catalytic tumor therapy and provides valuable insights for the advancement of future biomedical applications.