Donor-tailored MSC-EVs for osteoarthritis phenotypes: source heterogeneity, engineering, and precision therapy

Osteoarthritis (OA) is a highly heterogeneous degenerative joint disease comprising distinct clinical phenotypes. Recently, mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach. While MSC-EVs from diverse sources share fundamental therapeutic mechanisms, they also possess source-specific properties. However, the therapeutic efficacy of EVs is limited in treatments without considering the OA phenotypic diversity. This review aims to elucidate the biological heterogeneity of MSC-EVs derived from diverse tissues (bone marrow, adipose, umbilical cord, and others). By comparing their molecular mechanisms in OA, we outline a potential donor-tailored approach that may inform matching of MSC-EV sources to predominant OA phenotypes. Furthermore, to overcome the limitations of native EVs in targeted delivery and in vivo half-life, we apply frontier bioengineering paradigms, including cellular preconditioning, genetic engineering, cargo loading, and integration with biomaterial scaffolds. Collectively, these advanced methodologies significantly enhance the targeting capability, intra-articular retention, and phenotype-specific therapeutic potency of MSC-EVs. Finally, we delineate current challenges and future research directions, establishing a theoretical foundation to accelerate the clinical translation of donor-tailored MSC-EVs as a precise and effective therapeutic approach for OA.