Cartilage targeted grape skin-derived extracellular vesicles ameliorate osteoarthritis by attenuating chondrocyte senescence

Osteoarthritis (OA) is predominantly driven by chondrocyte senescence, accompanied by progressive cartilage degradation. Facing the substantial worldwide impact of this condition, creating sustainable and economical therapies has become increasingly urgent. Plant-derived extracellular vesicles (PEVs) present a highly attractive option, notably because they are readily sourced, exhibit minimal immunogenicity, boast excellent biocompatibility, and can be produced at scale. Crucially, these nanovesicles facilitate cell-to-cell signaling by shuttling inherent bioactive cargo. In our study, we propose to utilize grape skin-derived extracellular vesicles (GSEVs), a by-product of the food industry, as a new nanotherapeutic platform. By coupling GSEVs with a type II collagen-binding peptide (WYRGRL), we generated cartilage-tendency-enhancing W-GSEVs that increased their accumulation and retention time in articular chondrocytes. In vitro findings demonstrated that W-GSEVs attenuated chondrocyte senescence by reducing reactive oxygen species (ROS) production and inhibiting both IL-17 and TNF signaling pathways. In vivo experiments further demonstrated that intra-articular injection of W-GSEVs effectively mitigates chondrocyte senescence in OA mice, thereby protecting cartilage from breakdown, reducing abnormal bone growth, and normalizing subchondral bone remodeling. This treatment notably slowed OA advancement and helped maintain balanced matrix metabolism. This work not only repurposes agricultural waste into a high-value biomedical tool, but also highlights the clinical translational potential of PEVs as a scalable, low-immunogenic platform for OA treatment by directly targeting chondrocyte senescence.