BMSC-derived exosomal miR-27a-3p ameliorates osteoarthritis via dual regulation of chondrocyte protection and macrophage M1 polarization through TXNIP/NLRP3 signaling.

Osteoarthritis (OA) is a degenerative joint disorder marked by cartilage degradation and synovial inflammation, for which effective treatments remain limited. Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have emerged as promising cell-free therapies due to their immunomodulatory properties. In this study, we investigated whether exosomes from BMSCs overexpressing miR-27a-3p alleviate OA by targeting the TXNIP/NLRP3 axis in both chondrocytes and macrophages. BMSCs were transfected with miR-27a-3p mimics, and exosomes (Exos-miR-27a-3p) were isolated and characterized. Exos-miR-27a-3p were internalized by chondrocytes and directly targeted TXNIP, thereby reversing IL-1β-induced suppression of proliferation, migration, and matrix synthesis, while reducing catabolic factors. In macrophages, Exos-miR-27a-3p inhibited LPS-induced M1 polarization, decreased pro-inflammatory cytokines, and suppressed TXNIP/NLRP3-associated inflammasome activation, as indicated by reduced caspase-1 cleavage, IL-1β maturation/release and ASC speck formation. TXNIP overexpression partially reversed these protective effects. In a mouse model of OA, intra-articular injection of Exos-miR-27a-3p attenuated cartilage degeneration, preserved proteoglycan content, reduced M1 macrophages in synovial tissue, and suppressed TXNIP expression. Collectively, these findings suggest that BMSC-derived exosomal miR-27a-3p alleviates OA through a dual-cell mechanism involving direct chondrocyte protection and macrophage inflammatory reprogramming via the TXNIP/NLRP3 axis.