The Jekyll and Hyde of Extracellular Vesicles: Dual Roles as Disease Drivers and Therapeutic Saviors in Diabetic Brain.
Diabetes-associated cognitive impairment (DACI) represents a debilitating complication lacking effective therapeutics. Extracellular vesicles (EVs) demonstrate a paradoxical dual role in DACI pathophysiology. Under diabetic conditions, EVs secreted by metabolically dysregulated adipose tissue and activated circulating inflammatory cells deliver neurotoxic cargo (miR-9-3p, miR-125a-5p) inducing neuronal ferroptosis, synaptic loss, and blood-brain barrier disruption via MEK/ROCK signaling. Brain-derived EVs enriched in complement proteins and mitochondrial markers serve as minimally invasive diagnostic biomarkers validated in multicenter cohorts. Conversely, mesenchymal stem cell-derived and brain endothelial cell-derived EVs exhibit substantial therapeutic potential, attenuating neuroinflammation, promoting neurogenesis, and restoring cognitive function across preclinical models. Clinical translation confronts challenges in GMP-compliant manufacturing, regulatory harmonization, and standardized potency assays. Engineering strategies encompassing cargo optimization and surface modification for brain targeting offer transformative solutions. This review establishes an integrated framework for developing EV-based diagnostics and therapeutics to address this prevalent complication.