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

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.