Tissue-Derived Small Extracellular Vesicles: Emerging Regulators of Inter-Organ Crosstalk in Health and Disease

Small extracellular vesicles (sEVs; commonly referred to as "exosomes" in many studies) are nanoscopic messengers released by healthy and diseased cells that mediate intercellular communication by transferring proteins, lipids, and nucleic acids to local or distant recipient cells. In this narrative review, we synthesize recent evidence linking tissue-derived sEVs to neurological disorders (including neurodegeneration and traumatic brain injury), metabolic syndrome, cardiovascular diseases, cancers, and bone diseases, with a particular emphasis on CNS-periphery crosstalk across the blood-brain barrier. Compared with prior reviews that focus on single organ systems, we highlight cross-disease, cross-tissue mechanisms and summarize candidate biomarker cargos and therapeutic strategies in dedicated tables. While accumulating data support brain-body communication via sEVs, the concept of CNS-derived sEVs acting as a "third central efferent pathway" is presented here as an emerging hypothesis that complements-rather than replaces-neuronal and endocrine signaling. Overall, tissue-derived sEVs represent a promising but still evolving platform for diagnostic and therapeutic innovation, warranting standardized isolation/characterization and further clinical validation.