A mesoporous oxygen-vacancy-rich ZnO nanoplatform as a catalytic therapeutic hub for osteoarthritis therapy by TRIM15-targeted stem cell rejuvenation

<title>Abstract</title> <p> Osteoarthritis (OA) lacks disease-modifying treatments, partly because aging creates an oxidative-senescent joint niche that accelerates cartilage degeneration and weakens endogenous MSC-mediated repair. We found that aged OA cartilage harboured TRIM15-high MSC-like cells, whereas aged joint-derived MSCs exhibited zinc depletion, defective mitophagy and impaired chondrogenesis. To address these abnormalities, we developed oxygen-vacancy-rich mesoporous ZnO (meso-ZnO _v ) as an active therapeutic material capable of scavenging reactive oxygen species and restoring zinc homeostasis through Zn ²⁺ release. Here, we incorporated a Zn ²⁺ -dependent TRIM15-targeting DNAzyme into meso-ZnO _v and coated this active core with an ITGA2-enriched hybrid membrane to generate ZDM. ZDM preferentially accumulated in damaged cartilage and enhanced tissue penetration. It alleviated oxidative stress and senescence and restored cartilage matrix homeostasis, while re-establishing zinc homeostasis and rejuvenating aged MSCs. Mechanistically, ZDM reduced TRIM15 abundance and YAP nuclear localisation and restored SOX9 expression and PINK1-dependent mitophagy, thereby reversing MSC senescence and promoting chondrogenesis. In aged mouse and beagle OA models, ZDM improved joint function, preserved cartilage and subchondral bone, and reduced synovial inflammation. These findings establish a meso-ZnO _v -based nanotherapeutic strategy that couples microenvironmental restoration with stem-cell rejuvenation, offering a promising disease-modifying approach for age-associated OA. </p>