Not All Extracellular Vesicles Are Equal: A Narrative Comparative Review of Source-Dependent Function and Therapeutic...

Extracellular vesicles (EVs) are increasingly investigated as cell-free therapeutic platforms, yet EVs from different cellular sources are often considered functionally interchangeable despite substantial biological heterogeneity. This narrative comparative review evaluated how EV source influences molecular cargo, phenotype, biological function, therapeutic suitability, safety, and translational potential. PubMed/MEDLINE, Europe PMC, and OpenAlex were searched from inception through 14 August 2026, supplemented by targeted Google Scholar and backward and forward citation searching. Of the 9779 database records identified, 3799 duplicates were removed and 5980 unique records were screened. Sixty-seven database studies and three additional studies identified through supplementary searching met the criteria for direct within-study comparison of EVs from distinct parental cell or tissue sources. Across the 70 direct comparisons, source-associated differences in cargo, phenotype, target-cell responses, and therapeutic performance were frequently reported; however, the depth and consistency of supporting evidence varied substantially across source families and indications, with activity further influenced by cellular state, engineering, vesicle fraction, isolation method, and dose. Based on these findings, we propose EV-FIT+-Function, Indication, Trade-off, and Contra-Function-as an author-developed qualitative framework for rational EV source selection. No EV source is universally superior; therapeutic suitability depends on matching source- and product-specific biological characteristics and risks to the intended clinical objective.