An intelligent tribological hydrogel delivering 9,10-DiOH activates cuproptosis for comprehensive rheumatoid...

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by persistent synovial hyperplasia, severe oxidative stress, and progressive biomechanical destruction of articular cartilage. Current pharmacological interventions predominantly rely on systemic immunosuppression, which fails to address localized mechanical wear and suffers from rapid intra-articular clearance and off-target toxicity. Herein, we present a unified biological and materials-science strategy by engineering an intelligent, stimuli-responsive hydrogel composite (CS-RB/DiOH) that simultaneously restores joint tribology and modulates lipid metabolism. Through comprehensive chemical profiling, we identified 9,10-dihydroxyoctadecanoic acid (9,10-DiOH) as a core bioactive lipid mediator. Integrated multi-omics analyses reveal that 9,10-DiOH engages ferredoxin 1 (FDX1)-dependent cuproptosis, thereby suppressing NF-kB and MAPK inflammatory signaling, inhibiting osteoclastogenesis, and attenuating synovial fibroblast hyperproliferation. To overcome delivery barriers, 9,10-DiOH is conjugated into a chitosan-based polymeric network via dynamic covalent boronate ester bonds. This architecture enables RGD-mediated active targeting and temperature-, reactive oxygen species (ROS)-, and pH-triggered precision drug release. Crucially, the exposure of the lipid's hydrophobic alkyl chains at the interface provides robust biomimetic boundary lubrication, reducing the intra-articular coefficient of friction. In a murine RA model, this localized depot effectively alleviates synovitis, attenuates bone erosion, and helps preserve joint architecture. This work highlights a mechanism-driven therapeutic paradigm that synergizes metabolic cuproptosis induction with tribological restoration for comprehensive RA management.