Abstract
Osteoarthritis (OA) remains without disease-modifying sssstherapies, in part due to biological heterogeneity and a hostile joint microenvironment that undermines one-size-fits-all interventions. Extracellular vesicles (EVs) play a dual role in OA pathophysiology: endogenous EVs disseminate pro-inflammatory and catabolic signals that propagate cartilage degeneration, whereas therapeutic EVs most commonly derived from regenerative cell sources can deliver anti-inflammatory and anabolic cues. We frame this contrast as the EV paradox and argue that it represents a central translational challenge explaining why robust preclinical efficacy has not yet translated into consistent clinical benefit. We synthesize current evidence on EV biology in joint tissues, outcomes across preclinical models, and early human studies that demonstrate safety but limited efficacy. This analysis highlights key barriers to translation, including impaired EV function within inflamed and mechanically active joints, rapid clearance and limited tissue targeting, mismatch between animal models and human disease, and insufficient standardization of EV potency. Building on these insights, we propose a precision-medicine roadmap that emphasizes patient stratification, rational EV design, improved delivery strategies, and manufacturing frameworks linked to mechanism-anchored endpoints. Together, this framework reframes the EV paradox from a translational obstacle into a design principle for developing disease-modifying EV-based therapies for OA.