A biomimetic chondrocyte membrane-camouflaged tFNA nanoplatform for reprogramming the cartilage-synovium axis in osteoarthritis.

Osteoarthritis (OA) is a whole-joint disorder characterized by progressive cartilage degeneration and synovial remodeling, yet effective disease-modifying therapies remain unavailable. Mitochondrial dysfunction-driven chondrocyte senescence is increasingly recognized as a key driver of cartilage degeneration and pathological cartilage-synovium crosstalk. Here, we engineered a biomimetic, programmable nanoplatform, termed CM@THC, by loading hesperidin, a natural flavonoid with potent antioxidant activity, into tetrahedral framework nucleic acids (tFNAs) and subsequently cloaking the nanocomplex with chondrocyte membranes (CMs). This hierarchical design combines the programmable drug-delivery capacity of tFNAs with the homologous targeting and biointerfacial properties of membrane camouflage, thereby improving nanocomplex stability, cellular internalization, and intra-articular retention. Functionally, CM@THC restored redox homeostasis and PINK1/Parkin-associated mitophagy in IL-1β-stimulated chondrocytes, attenuating cellular senescence and extracellular matrix imbalance while limiting the secondary profibrotic activation of fibroblast-like synoviocytes (FLSs). Collectively, these findings establish a membrane-camouflaged tFNA strategy for natural-product delivery and identify CM@THC as a biomimetic, mitochondria-protective nanotherapeutic that disrupts the pathological cartilage-synovium axis in OA.