ArticleMaterials today. Bio2026
Epigenetic-metabolic coupling by SOX3/WDR5-SIRT5 signaling mediates the therapeutic effects of TGFβ-targeted exosomal nanoparticles in osteoarthritis.
Article in Materials today. Bio, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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