Exosomes and Small Extracellular Vesicles as an Alternative to Mesenchymal Stromal Cell Therapy in Knee Osteoarthritis: From Biological Rationale to Clinical Evidence.

Knee osteoarthritis (KOA) is a leading cause of pain and disability worldwide, and current treatments remain largely symptomatic, with no disease-modifying therapy established for routine use. This narrative review evaluates extracellular vesicles (EVs) as biological nanocarriers and a cell-free alternative to mesenchymal stromal cell therapy for KOA by examining the biological rationale, preclinical evidence, clinical studies, and current methodological and regulatory requirements. Preclinical findings indicate that EVs may exert immunomodulatory, anti-inflammatory, and chondroprotective effects, supporting their potential to influence joint homeostasis. The review also summarizes current recommendations for EV nomenclature, characterization, and quality control in accordance with the Minimal Information for Studies of EVs 2023 guidelines and highlights key translational challenges, including scalable manufacturing, potency assessment, and regulatory compliance. Clinical evidence to date suggests a favorable safety profile, but efficacy data remain limited and inconsistent; a randomized placebo-controlled trial showed no superiority over placebo, whereas small early human studies suggested possible benefit in selected cases. Overall, EVs represent a promising cell-free strategy for KOA, but current evidence is insufficient to support routine clinical use, emphasizing the need for standardized production, validated potency assays, and robust randomized clinical trials.