Brain organoids as models of extracellular vesicle–mediated human neural communication

: Cellular communication orchestrates human brain development through complex interactions involving adhesion molecules, signaling ligands, extracellular matrix, and extracellular vesicles. While intrinsic genetic programs governing neural differentiation are well characterized, the roles of extrinsic, non-cell-autonomous signaling, particularly extracellularmediated communication, remain poorly understood. Here, we review recent advances in three-dimensional brain organoids derived from human pluripotent stem cells as physiologically relevant models that recapitulate key aspects of human neurodevelopment, enabling detailed study of extracellular vesicle-mediated intracellular signaling. We highlight how organoid systems facilitate the investigation of extracellular vesicle cargo dynamics and their influence on neural cell fate, migration, and circuit assembly, as well as their involvement in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. These insights show the potential of brain organoids to unravel complex cellular interactions and inform biomarkers discovery and therapeutic strategies for neurological diseases.