Copper(II)\nOxide Spindle-like Nanomotors Decorated\nwith Calcium Peroxide Nanoshell as a New Nanozyme with Photothermal\nand Chemodynamic Functions Providing ROS Self-Amplification, Glutathione\nDepletion, and Cu(I)/Cu(II) Recycling

Uniform, mesoporous\ncopper(II) oxide nanospindles (CuO NSs) were\nsynthesized via a method based on templated hydrothermal oxidation\nof copper in the presence of monodisperse poly(glycerol dimethacrylate-<i>co</i>-methacrylic acid) nanoparticles (poly(GDMA-<i>co</i>-MAA) NPs). Subsequent decoration of CuO NSs with a CaO<sub>2</sub> nanoshell (CuO@CaO<sub>2</sub> NSs) yielded a nanozyme capable of\nCu(I)/Cu(II) redox cycling. Activation of the Cu(I)/Cu(II) cycle by\nexogenously generated H<sub>2</sub>O<sub>2</sub> from the CaO<sub>2</sub> nanoshell significantly enhanced glutathione (GSH) depletion.\nCuO@CaO<sub>2</sub> NSs exhibited a 2-fold higher GSH depletion rate\ncompared to pristine CuO NSs. The generation of oxygen due to the\ncatalase (CAT)-like decomposition of H<sub>2</sub>O<sub>2</sub> by\nCuO@CaO<sub>2</sub> NSs resulted in a self-propelled diffusion behavior,\ncharacteristic of a H<sub>2</sub>O<sub>2</sub> fueled nanomotor. These\nnanostructures exhibited both peroxidase (POD)-like and CAT-like activities\nand were capable of self-production of H<sub>2</sub>O<sub>2</sub> in\naqueous media via a chemical reaction between the CaO<sub>2</sub> nanoshell\nand water. Usage of the self-supplied H<sub>2</sub>O<sub>2</sub> by\nthe POD-like activity of CuO@CaO<sub>2</sub> NSs amplified the generation\nof toxic hydroxyl (<sup>•</sup>OH) radicals, enhancing the\nchemodynamic effect within the tumor microenvironment (TME). The CAT-like\nactivity provided a source of self-supplied O<sub>2</sub> via decomposition\nof H<sub>2</sub>O<sub>2</sub> to alleviate hypoxic conditions in the\nTME. Under near-infrared laser irradiation, CuO@CaO<sub>2</sub> NSs\nexhibited photothermal conversion properties, with a temperature elevation\nof 25 °C. The combined GSH depletion and H<sub>2</sub>O<sub>2</sub> generation led to a more effective production of <sup>•</sup>OH radicals in the cell culture medium. The chemodynamic function\nwas further enhanced by an elevated temperature. To assess the therapeutic\npotential, CuO@CaO<sub>2</sub> NSs loaded with the photosensitizer,\nchlorine e6 (Ce6), were evaluated against T98G glioblastoma cells.\nThe synergistic combination of photodynamic, photohermal, and chemodynamic\nmodalities using CuO@CaO<sub>2</sub>@Ce6 NSs resulted in cell death\nhigher than 90% under in vitro conditions.