Curcumin-Loaded GelMA Microspheres Alleviate Osteoarthritis: Transcriptomic Evidence for Immune Microenvironment Remodeling and ECM Homeostasis Restoration.

Osteoarthritis (OA) progression is driven by inflammatory mediators and immune dysregulation within the joint. Curcumin (Cur) possesses multi-target therapeutic potential. However, its clinical application is limited by poor solubility and a short half-life. In this study, we developed injectable Cur-loaded GelMA microspheres (Cur-MS) and evaluated their effects in IL-1β stimulated chondrocytes, cartilage organoids, and a monosodium iodoacetate (MIA) induced rat OA model, complemented by public transcriptomic analysis (GSE114007). The Cur-MS demonstrated uniform size distribution, favorable biocompatibility, and sustained curcumin release. Treatment with Cur-MS significantly reduced chondrocyte apoptosis, reactive oxygen species levels, and hypertrophic markers; restored COL-II and ACAN synthesis; and downregulated MMP13 and inflammatory gene expression. In vivo, Cur-MS improved joint space, alleviated pain, decreased synovial CD68 positive macrophage infiltration and levels of IL-6 and TNF-α, and enhanced chondrogenic gene expression. Public transcriptomic data corroborated these findings, revealing upregulation of MMP13 and downregulation of SOX9 in OA cartilage, consistent with our experimental targets. Collectively, this study provides the first multi-model evidence combined with transcriptomic validation, demonstrating that Cur-MS not only directly protects chondrocytes and restores extracellular matrix homeostasis but also modulates the joint inflammatory immune microenvironment. These findings suggest that Cur-MS represents a promising locally sustained-release therapeutic strategy for OA.