Cerium Dioxide Nanoparticles-Based Inspector Enhances Mitochondrial Quality Control to Maintain Chondrocyte Homeostasis in Osteoarthritis Therapy.

Imbalanced mitochondrial quality control is strongly linked to the onset and development of osteoarthritis (OA). However, current research primarily focuses on local cartilage repair and phenotype maintenance, lacking a systematic approach to subcellular mitochondrial quality control. To address this, the present study proposes a mitochondrial quality control strategy based on nanozyme hydrogel microspheres ("mitochondrial inspector"), constructed through electrostatic self-assembly, incorporation of dynamic diselenide bonds, and microfluidic technology. The mitochondrial oxidative stress microenvironment is improved by cerium dioxide nanoparticles and combined with metformin to activate autophagy to clear persistently dysfunctional mitochondria, thereby inhibiting OA progression. In vitro results showed that "mitochondrial inspector" not only significantly improved the oxidative stress microenvironment of chondrocytes, but also efficiently scavenged the damaged mitochondria, increased the mitochondrial membrane potential by over 20-fold, and notably improved the mitochondrial function and chondrocyte homeostasis. In a rat OA model, minimally invasive intra-articular injection of the "mitochondrial inspector" effectively regulated mitochondrial quality, alleviated cartilage matrix degradation, reduced osteophyte formation by ≈80%, and reduced the Mankin score for cartilage damage by over 70%. In summary, this study presents a novel nanozyme microsphere-based mitochondrial quality control strategy for the treatment of OA, providing new insights for subcellular therapies for other aging-related diseases.