Oxygen vacancy-engineered cerium oxide mediated by copper-platinum exhibit enhanced SOD/CAT-mimicking activities to regulate the microenvironment for osteoarthritis therapy.

Cerium oxide (CeO) nanospheres have limited enzymatic activity that hinders further application in catalytic therapy, but they have an "oxidation switch" to enhance their catalytic activity by increasing oxygen vacancies. In this study, according to the defect-engineering strategy, we developed PtCuO/CeO nanozymes as highly efficient SOD/CAT mimics by introducing bimetallic copper (Cu) and platinum (Pt) into CeO nanospheres to enhance the oxygen vacancies, in an attempt to combine near-infrared (NIR) irradiation to regulate microenvironment for osteoarthritis (OA) therapy. As expected, the Cu and Pt increased the Ce/Ce ratio of CeO to significantly enhance the oxygen vacancies, and simultaneously CeO (111) facilitated the uniform dispersion of Cu and Pt. The strong metal-carrier interaction synergy endowed the PtCuO/CeO nanozymes with highly efficient SOD/CAT-like activity by the decreased formation energy of oxygen vacancy, promoted electron transfer, the increased adsorption energy of intermediates, and the decreased reaction activation energy. Besides, the nanozymes have excellent photothermal conversion efficiency (55.41%). Further, the PtCuO/CeO antioxidant system effectively scavenged intracellular ROS and RNS, protected mitochondrial function, and inhibited the inflammatory factors, thus reducing chondrocyte apoptosis. In vivo, experiments demonstrated the biosafety of PtCuO/CeO and its potent effect on OA suppression. In particular, NIR radiation further enhanced the effects. Mechanistically, PtCuO/CeO nanozymes reduced ras-related C3 botulinum toxin substrate 1 (Rac-1) and p-p65 protein expression, as well as ROS levels to remodel the inflammatory microenvironment by inhibiting the ROS/Rac-1/nuclear factor kappa-B (NF-κB) signaling pathway. This study introduces new clinical concepts and perspectives that can be applied to inflammatory diseases.