Multimodal hydrogel modulation of extracellular vesicle cargo to arrest post-traumatic osteoarthritis in murine models

Effective prophylactic interventions for exercise-induced joint damage and preclinical osteoarthritis remain elusive, as abnormal mechanical loading drives pathology through a dual pyroptotic loop between chondrocytes and macrophages. We present PMUC, a mechano-responsive lubricating hydrogel engineered for graded joint protection and repair. Mimicking native lubrication, intra-articular PMUC forms a persistent hydration layer that dissipates mechanical stress. Under pathological load, stress-induced reactive oxygen species trigger mannose and nanocomplex release. This cascade activates the hexosamine biosynthetic pathway, suppressing Caspase-3/GSDME-mediated chondrocyte pyroptosis while concurrently reprogramming macrophage-derived extracellular vesicles. Enriched with XIAP and OTULIN proteins, these in situ-generated extracellular vesicles act as intercellular messengers that disrupt the inflammatory cycle and facilitate matrix regeneration. In preclinical rat models of high-load exercise and post-traumatic OA, PMUC prevents cartilage erosion and achieves full regeneration with restored locomotion within eight weeks. Here we show that PMUC integrates adaptive lubrication with stress-triggered immune-metabolic modulation, offering a first‑in‑class strategy to protect joints and alleviate early OA. Here, the authors develop a mechano-responsive lubricating hydrogel that releases bioactive molecules under joint stress to interrupt the inflammatory cycle is osteoarthritis. In rat models, it prevents cartilage damage and restores motor function within eight weeks, offering a potential strategy for early osteoarthritis intervention.