Mammalian cell-derived extracellular vesicles remodel the immune-repair microenvironment in osteoarthritis: from pathological signal transmission to regenerative therapy.

Osteoarthritis is a whole-joint disease involving articular cartilage, synovium, subchondral bone, fat pad, meniscus, blood vessels, and sensory nerves. Its core pathology is not simply passive wear of the cartilage matrix, but rather reciprocal driving forces among mechanical stress, low-grade inflammation, cellular senescence, immunometabolic reprogramming, and failure of endogenous repair. As lipid bilayer-enclosed intercellular information carriers, Extracellular vesicles (EVs) carry proteins, lipids, nucleic acids, and metabolites, establishing a communication network among joint tissues that is source-dependent and context-dependent. In the osteoarthritic state, EVs released by inflammatory synovial fibroblasts, macrophages, stressed chondrocytes, osteocytes, and vascular endothelial cells propagate pro-inflammatory, catabolic, senescence, and mitochondrial damage signals, driving synovitis, cartilage matrix degradation, abnormal subchondral bone remodeling, and vascular invasion, thus forming a self-sustaining pathological EV cycle. Conversely, EVs derived from mesenchymal stromal cells (MSCs), regulatory macrophages, and other therapeutic cells can curb excessive inflammation, modulate macrophage status, restore chondrocyte autophagy and mitochondrial quality control, attenuate apoptosis, ferroptosis, and senescence, and translate immunosuppression into regenerative initiation signals by re-establishing extracellular matrix metabolism, recruiting endogenous repair cells, and coordinating osteochondral interface remodeling. In recent years, donor cell preconditioning, nucleic acid and protein cargo editing, cartilage-targeted modification, and hydrogel sustained-release systems have further improved the efficacy, tissue selectivity, and intra-articular retention of EVs. However, EV heterogeneity, inconsistent nomenclature and isolation methods, non-uniform dosage units, lack of potency assays, and insufficient long-term safety evidence still limit clinical translation. Focusing on the main thread of "pathological EV cycle - immune resetting - regenerative initiation", this review systematically elaborates the dual roles of EVs in the osteoarthritis immune-repair ecosystem and discusses key issues from mechanistic research and engineering design to clinical-grade manufacturing, with the aim of providing a new theoretical framework for disease-modifying therapy of osteoarthritis.