Modulating the synovial ROS-NO-RNS network attenuates fibroblast-like synoviocyte pyroptosis and osteoarthritis progression.

Osteoarthritis (OA) is characterized by persistent synovial inflammation and disturbed redox homeostasis, yet most redox-directed interventions predominantly target reactive oxygen species (ROS) and provide limited control over the interconnected ROS-nitric oxide (NO)-reactive nitrogen species (RNS) network. Here, we developed Mn@GaMOF, a gallium-based metal-organic framework bearing highly dispersed mixed-valence Mn sites, to coordinately regulate the synovial nitro-oxidative microenvironment. Post-synthetic Mn incorporation markedly enhanced the superoxide dismutase (SOD)- and catalase (CAT)-like activities and peroxynitrite (ONOO-)-scavenging capacity of GaMOF, whereas the GaMOF framework suppressed inducible nitric oxide synthase (iNOS) expression and excessive NO production. This complementary regulation reduced ROS, NO, and RNS accumulation and attenuated nitro-oxidative stress in inflammatory macrophages and fibroblast-like synoviocytes (FLSs). In macrophages, Mn@GaMOF suppressed inflammatory cytokine production and reduced M1-associated inflammatory features while enhancing selected M2-associated markers. In primary FLSs, Mn@GaMOF attenuated nitro-oxidative stress, inflammatory and catabolic activation, wound-closure responses, and NLRP3/caspase-1/GSDMD-associated pyroptosis. Consistently, conditioned medium derived from Mn@GaMOF-treated FLSs under pyroptotic stimulation preserved chondrocyte matrix homeostasis and proliferation while reducing catabolic activation and cellular senescence. In a destabilization of the medial meniscus mouse model, intra-articular Mn@GaMOF alleviated pain-related behaviors and gait abnormalities and mitigated synovitis, cartilage degeneration, osteophyte formation, and subchondral bone sclerosis, accompanied by reduced synovial 3-nitrotyrosine accumulation and NLRP3 expression. Collectively, these findings identify coordinated regulation of the synovial ROS-NO-RNS network as a redox-directed strategy associated with suppression of FLS pyroptosis and pathological synovium-cartilage crosstalk, highlighting this interconnected redox network as a therapeutically relevant axis in OA.