Tiny Travelers, Big Impact: Physiological Effects of Extracellular Vesicles on the Blood-Brain Barrier.

The blood-brain barrier [BBB] is a highly specialized structure that regulates the influx and efflux of nutrients and metabolic waste to maintain homeostasis of the central nervous system. This selective permeability of the BBB is sustained by tight junctions that are supported by pericytes and astrocytes. Recently, extracellular vesicles have emerged as mediators of intercellular communication across and within the BBB. This review examines the bidirectional transport of EVs across the BBB and the distinct functional impacts of blood-borne EVs. On the luminal side, circulating EVs derived from platelets, erythrocytes, and leukocytes convey systemic signals to the neurovasculature. Platelet-derived EVs deliver growth factors and lipid mediators that promote vascular repair and modulate adaptive immunity during endothelial disruption. Erythrocyte-derived EVs selectively shed surface markers like CD47 to regulate cellular turnover while simultaneously providing phosphatidylserine that maintains hemostasis and nitric oxide bioavailability. Meanwhile, leukocytic-derived EVs protect and transport immunological cargo, such as MHC complexes and cytokines, functioning as critical sensors and amplifiers of immune surveillance at the vascular interface. Together, these circulating EV populations influence endothelial signaling, transporter expression, and tight junction integrity from the vascular side. Conversely, on the abluminal side, the roles of brain parenchymal-derived EVs secreted by astrocytes, pericytes, neurons, and microglia are explored in regulating local neurovascular coupling, vascular tone, and endothelial responsiveness. Within this microenvironment, astrocyte-derived EVs provide neurotrophic and neuroprotective support by delivering angiogenic factors and cytoprotective chaperone proteins like HSP70 to protect cells from mechanical and oxidative stress. Pericyte-derived EVs preserve microvascular barrier integrity by transporting regulatory microRNAs and angiopoietin-1 to directly upregulate endothelial tight junction proteins. Furthermore, neuron-derived EVs participate in activity-dependent signaling, transferring vital microRNAs to endothelial cells to promote vascular stability and support synaptic plasticity. By framing the BBB as an active communication system, this review underscores how peripheral and central EVs integrate systemic and neural environments, highlighting their fundamental roles in BBB physiology and, beyond, their profound implications as biomarkers of CNS distress and programmable vehicles for targeted drug delivery.