Epigenetic-metabolic coupling by SOX3/WDR5-SIRT5 signaling mediates the therapeutic effects of TGFβ-targeted exosomal nanoparticles in osteoarthritis.

The development of targeted nanotherapeutics capable of restoring chondrocyte homeostasis represents a major challenge in osteoarthritis (OA) treatment. In this study, we engineered a transforming growth factor-β (TGF-β) receptor-targeted exosome-nanoparticle hybrid system (TGFβ-Exo-NP) derived from chondrocytes and systematically evaluated its therapeutic efficacy and molecular mechanism. TGFβ-Exo-NP displayed uniform nanoscale morphology, favorable surface charge, and controlled release properties, with robust chondrocyte-specific uptake mediated by transforming growth factor-β receptor (TGF-βR) targeting. Functionally, TGFβ-Exo-NP markedly restored mitochondrial function, increased adenosine triphosphate (ATP) production, and inhibited apoptosis and pyroptosis in IL-1β-challenged chondrocytes, while promoting anabolic extracellular matrix synthesis. Integrated ChIP-seq, RNA-seq, and proteomic analyses demonstrated that TGFβ-Exo-NP activated a SOX3-driven epigenetic program involving histone H3 lysine 4 trimethylation (H3K4me3) enrichment and SIRT5 upregulation, thereby reprogramming mitochondrial metabolism. WDR5 was identified as a key exosomal effector protein required for chromatin activation and metabolic recovery. In vivo, TGFβ-Exo-NP significantly ameliorated cartilage destruction and subchondral bone remodeling in a destabilization of the medial meniscus (DMM) rat model, with improved gait performance and histological outcomes. These results establish a multifunctional exosome-based nanosystem as a precision therapeutic strategy and provide mechanistic insights into epigenetic-metabolic reprogramming in OA.