Extracellular Vesicle Communication at the Neural Graft-Host Interface: From Bidirectional Paracrine Signaling to Graft Fate and Neural Circuit Integration.

Neural cell transplantation is progressing from nonspecific trophic support toward regionally defined cell replacement and functional circuit reconstruction. Yet transplanted cells do not develop in isolation; they remain embedded within a dynamic host environment composed of neurons, glia, vascular-associated cells, cerebrospinal fluid, and systemic signals. Extracellular vesicles (EVs) may provide a membrane-enclosed route for this reciprocal communication by transferring nucleic acids, proteins, lipids, and organelle-associated cargo across the graft-host interface. Moving beyond EVs as cell-free therapeutics, this review critically examines evidence for bidirectional EV communication between living neural grafts and their hosts, asking whether its effects extend from early niche regulation to donor-cell fate and functional integration. Available evidence is markedly asymmetric. A limited number of genuine transplantation studies demonstrate transfer of graft-associated EV signals to host myeloid cells, neurons, and endothelial cells, with inflammatory, metabolic, vascular, and pathological consequences. In contrast, host-to-graft EV regulation is supported predominantly by studies of endogenous or cultured neural precursors, which identify plausible mechanisms governing survival, migration, metabolic adaptation, and lineage choice but do not yet establish durable regulation of genuine donor cells in vivo. Because EV activity depends on cargo composition, recipient-cell recognition, uptake, and productive intracellular release, particle uptake alone is insufficient evidence of functional delivery. We therefore distinguish EV causality from graft integration as two independent evidence axes. Progress will depend less on demonstrating that EVs are biologically active than on establishing when source-defined EV communication is necessary for donor-cell fate, structural integration, and functional recovery.