Extracellular vesicles for liquid biopsy in major depressive disorder: Human evidence and clinical translation.

Major depressive disorder is diagnosed through clinical interview and symptom-based criteria. The search for peripheral biomarkers that might complement this assessment has identified extracellular vesicles (EVs) as a promising liquid biopsy platform, as they carry microRNAs, proteins, and other molecular cargo that may reflect disease-relevant biology. This narrative review critically appraises the human studies examining EV abundance, size, miRNA cargo, and protein profiles in MDD. We examine how pre-analytical variability, inconsistent isolation methods, and uncertain brain-enrichment specificity have limited cross-study convergence and independent replication. Translational readiness is evaluated against established biomarker development frameworks, from analytical validity through clinical utility. We argue that EV profiling should be integrated with clinical phenotyping, neuroimaging, and digital measures within precision psychiatry rather than deployed as a standalone diagnostic tool, and we outline a roadmap for standardization, multicenter validation, and clinical translation.