Aptamer-functionalized apoptotic vesicles ameliorate osteoarthritis via resuming mitochondria OXPHOS of chondrocytes

Emerging evidence suggests that osteoarthritis (OA) progression is critically associated with disruptions of cartilage matrix homeostasis caused by mitochondrial impairment in chondrocytes. Apoptotic vesicles (apoVs) derived from mesenchymal stem cells (MSCs) have exhibited great therapeutic promising for tissue regeneration and osteoarticular diseases. However, their poor ability targeting chondrocytes and short-time retention in joint cavity hinder further clinical translation. As a chemically synthesized nucleic acid, aptamer tgg2 demonstrated a robust specificity binding with chondrocytes. In this study, our team successfully functionalized apoVs with tgg2 (tgg2@apoVs) via Schiff base reaction with high conjugation efficiency and fabricated an injectable sustained-release system based on hyaluronic acid methacryloyl (HAMA) hydrogels. tgg2@apoVs significantly promoted chondrocyte extracellular matrix synthesis and improved mitochondrial oxidative phosphorylation (OXPHOS) in vitro. The HAMA injectable hydrogels compounded with tgg2@apoVs remarkedly alleviated OA symptoms in vivo. The potential molecular mechanism of apoVs' improvement in mitochondrial energy metabolism of chondrocytes is preliminarily investigated. Specifically, apoVs activate transcriptional factor Yin Yang 1 (YY1) to up-regulate the expression of Cox7c, a key subunit of complex IV in electron transport chain, thereby augmenting mitochondrial OXPHOS. In conclusion, the tgg2@apoVs' sustained-release system provides a cost-effective solution for OA treatment, and the elucidation of the molecular mechanism underlying apoVs' enhancement of chondrocyte OXPHOS offers insights for broader applications in energy metabolism-related diseases.