Spermidine-encapsulated chondroitin sulfate methacryloyl hydrogel delivery system for remodeling bone homeostasis in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation, progressive cartilage degradation, and osteoclast-mediated bone erosion. While current systemic therapies alleviate inflammation, they often fail to prevent structural joint damage or promote local tissue regeneration. Herein, we developed a chondroitin sulfate methacryloyl (ChSMA) hydrogel-based delivery system encapsulating spermidine (SPD), a naturally occurring polyamine with emerging anti-inflammatory, senescence-attenuating, and chondroprotective properties, to achieve localized and sustained treatment of RA-related joint destruction. Using an RA-mimicking co-culture model comprising RA patient-derived synovial organoids and chondrocytes, we demonstrated that ChSMA@SPD effectively attenuated chondrocyte apoptosis and suppressed the expression of pro-inflammatory cytokines and matrix metalloproteinases (MMPs). In addition, ChSMA@SPD significantly inhibited osteoclast differentiation <i>in vitro</i> using primary bone marrow-derived monocytes from mice by downregulating dendritic cell-specific transmembrane protein (DC-STAMP) expression. <i>In vivo</i> studies using the collagen-induced arthritis (CIA) mouse model further confirmed that intra-articular administration of ChSMA@SPD reduced arthritis severity, preserved cartilage integrity, and mitigated joint inflammation. Furthermore, network pharmacology and molecular docking analyses identified key signaling pathways and potential molecular targets of SPD, such as TGFB2, XIAP, MMP8, and PLA2G1B. Collectively, our findings highlight ChSMA@SPD as a dual-functional hydrogel platform that simultaneously protects cartilage and suppresses bone resorption, offering a promising localized therapeutic strategy for RA treatment.