Exosomes in depression: mechanistic insights, diagnostic potential, and therapeutic opportunities

Exosomes are increasingly recognized as critical mediators of intercellular communication within the central nervous system and along the brain-periphery axis, with emerging relevance to the pathophysiology of depression. These nanoscale extracellular vesicles transport bioactive cargo-including microRNAs (miRNAs), proteins, lipids, and metabolites-that can modulate neuroinflammatory signaling, synaptic remodeling, hypothalamic-pituitary-adrenal (HPA) axis dynamics, and gut-brain communication. Converging evidence from human and preclinical studies suggests that alterations in circulating and brain-derived exosomal cargo are associated with major depressive disorder (MDD) and secondary depression following neurological insults such as traumatic brain injury (TBI), implicating shared inflammatory and synaptic pathways alongside distinct etiological drivers. Circulating neuron-enriched exosomes carrying miRNAs such as miR-16 and miR-124 have been proposed as minimally invasive biomarkers reflecting brain-relevant molecular alterations. However, most human data remain cross-sectional and associative, with limited longitudinal replication and incomplete validation of cellular origin. Therapeutically, mesenchymal stem cell (MSC)-derived exosomes demonstrate antidepressant-like effects in rodent models through modulation of microglial activation, enhancement of synaptic plasticity, and attenuation of neuroinflammatory cascades. Engineered exosomes further offer a potential platform for targeted delivery of anti-inflammatory or neuroplasticity-enhancing cargo. Induced pluripotent stem cell (iPSC)-derived exosomes represent a potentially scalable and standardizable therapeutic platform. Despite this promise, substantial barriers impede clinical translation. Isolation workflows-including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture-vary in yield, purity, and reproducibility, complicating cross-cohort comparability. Moreover, definitive attribution of vesicle origin in peripheral biofluids remains technically constrained, and standardized reporting frameworks are inconsistently applied. Advances in multi-omics profiling, high-throughput sequencing, mass spectrometry, and spatially resolved molecular analyses may improve mechanistic resolution and biomarker robustness. Collectively, exosome research in depression resides at an early but rapidly evolving translational stage. Rigorous methodological standardization, longitudinal cohort validation, and mechanistic dissection across primary and injury-related depression will be essential to determine whether exosome-based diagnostics and therapeutics can fulfill their potential within precision psychiatry.