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Osteoarthritis (OA) is a degenerative joint disorder characterized by cartilage degradation and subchondral bone alterations. As current OA treatment mainly focuses on damaged cartilage repair, novel therapeutic strategies targeting microenvironmental instability and chondrocyte dysfunction are needed. This study investigated the therapeutic potential of platelet-derived growth factor (PDGF)-BB, delivered via sodium hyaluronate (SH), in modulating OA chondrocyte microstructure and cytoskeletal dynamics. Utilizing a high-throughput 3D chondrogenic organoid model, we simulated the in vivo cartilage microenvironment to assess the sustained efficacy of PDGF-BB. In vitro and in vivo analyses demonstrated that PDGF-BB significantly stabilized the hypoxic cartilage microenvironment by suppressing F-actin formation and chondrocyte dedifferentiation. Mechanistically, PDGF-BB exerted its effects through oxygen-dependent regulation of HIF-1α/SCIN signaling and inhibition of the RhoA/ROCK pathway, thereby preserving chondrocyte phenotype and extracellular matrix integrity. Furthermore, SH-mediated PDGF-BB delivery extended therapeutic duration, reducing injection frequency while maintaining comparable efficacy to PDGF-BB alone. These findings highlight the role of PDGF-BB in microenvironmental stabilization and indicate SH as an effective delivery vehicle for prolonged OA management. Our findings provide a foundation for clinical translation of PDGF-based therapies, emphasizing combination strategies to optimize treatment outcomes in degenerative joint diseases.