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--methacrylic acid) nanoparticles (poly(GDMA--MAA) NPs). Subsequent decoration of CuO NSs with a CaO nanoshell (CuO@CaO NSs) yielded a nanozyme capable of Cu(I)/Cu(II) redox cycling. Activation of the Cu(I)/Cu(II) cycle by exogenously generated HO from the CaO nanoshell significantly enhanced glutathione (GSH) depletion. CuO@CaO 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 HO by CuO@CaO NSs resulted in a self-propelled diffusion behavior, characteristic of a HO fueled nanomotor. These nanostructures exhibited both peroxidase (POD)-like and CAT-like activities and were capable of self-production of HO in aqueous media via a chemical reaction between the CaO nanoshell and water. Usage of the self-supplied HO by the POD-like activity of CuO@CaO 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 O via decomposition of HO to alleviate hypoxic conditions in the TME. Under near-infrared laser irradiation, CuO@CaO NSs exhibited photothermal conversion properties, with a temperature elevation of 25 °C. The combined GSH depletion and HO 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@CaO 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@CaO@Ce6 NSs resulted in cell death higher than 90% under in vitro conditions.