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

Uniform, mesoporous copper(II) oxide nanospindles (CuO NSs) were synthesized via a method based on templated hydrothermal oxidation of 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 CaO₂ nanoshell (CuO@CaO₂ NSs) yielded a nanozyme capable of Cu(I)/Cu(II) redox cycling. Activation of the Cu(I)/Cu(II) cycle by exogenously generated H₂O₂ from the CaO₂ nanoshell significantly enhanced glutathione (GSH) depletion. CuO@CaO₂ NSs exhibited a 2-fold higher GSH depletion rate compared to pristine CuO NSs. The generation of oxygen due to the catalase (CAT)-like decomposition of H₂O₂ by CuO@CaO₂ NSs resulted in a self-propelled diffusion behavior, characteristic of a H₂O₂ fueled nanomotor. These nanostructures exhibited both peroxidase (POD)-like and CAT-like activities and were capable of self-production of H₂O₂ in aqueous media via a chemical reaction between the CaO₂ nanoshell and water. Usage of the self-supplied H₂O₂ by the POD-like activity of CuO@CaO₂ NSs amplified the generation of toxic hydroxyl (^•OH) radicals, enhancing the chemodynamic effect within the tumor microenvironment (TME). The CAT-like activity provided a source of self-supplied O₂ via decomposition of H₂O₂ to alleviate hypoxic conditions in the TME. Under near-infrared laser irradiation, CuO@CaO₂ NSs exhibited photothermal conversion properties, with a temperature elevation of 25 °C. The combined GSH depletion and H₂O₂ generation led to a more effective production of ^•OH radicals in the cell culture medium. The chemodynamic function was further enhanced by an elevated temperature. To assess the therapeutic potential, CuO@CaO₂ NSs loaded with the photosensitizer, chlorine e6 (Ce6), were evaluated against T98G glioblastoma cells. The synergistic combination of photodynamic, photohermal, and chemodynamic modalities using CuO@CaO₂@Ce6 NSs resulted in cell death higher than 90% under in vitro conditions.