Combined adipose- and umbilical cord-derived extracellular vesicles modulate inflammatory and chondrogenic signaling to promote cartilage repair.

Introduction: Articular cartilage has a limited intrinsic capacity for regeneration following injury, particularly in cases of severe defects. Exosome-based therapy has emerged as a promising cell-free regenerative strategy, with increasing preclinical evidence supporting its therapeutic potential in cartilage repair. As previous studies have indicated that human adipose-derived mesenchymal stem cells (hADSCs) secrete regenerative factors, whereas human umbilical cord-derived mesenchymal stem cells (hUCMSCs) exert immunomodulatory effects, the combined use of exosomes from these two sources may have complementary therapeutic benefits. Methods: In this study, exosome-enriched extracellular vesicles (EVs) isolated from hADSCs and hUCMSCs were combined, characterized, and evaluated in a cartilage defect model. The isolated EVs displayed a characteristic cup-shaped morphology under transmission electron microscopy, a size distribution ranging from 30 to 200 nm, and high expression levels of the exosomal markers CD9, CD63, and CD81. Results: Treatment with the combined EVs formulation promoted the regeneration of medial femoral condyle defects at 12 weeks post-injury compared to untreated controls, as demonstrated by an improved macroscopic appearance and scoring, radiographic evaluation, and increased deposition of total collagen, glycosaminoglycans, and aggrecan. Conclusion: The findings provide proof-of-concept evidence that a combined hADSC- and hUCMSC-derived EVs formulation represents a feasible cell-free approach to cartilage repair.