Extracellular vesicles set the stage for brain plasticity and recovery by multimodal signalling

Extracellular vesicles (EVs) are extremely versatile naturally occurring membrane particles that convey complex signals between cells. EVs of different cellular sources are capable of inducing striking therapeutic responses in neurological disease models. Differently from pharmacological compounds that act by modulating defined signalling pathways, EV-based therapeutics possess multiple abilities via a variety of effectors, thus allowing the modulation of complex disease processes that may have very potent effects on brain tissue recovery. When applied in vivo in experimental models of neurological diseases, EV-based therapeutics have revealed remarkable effects on immune responses, cell metabolism and neuronal plasticity. This multimodal modulation of neuroimmune networks by EVs profoundly influences disease processes in a highly synergistic and context-dependent way. Ultimately, the EV-mediated restoration of cellular functions helps to set the stage for neurological recovery. With this review we first outline the current understanding of the mechanisms of action of EVs, describing how EVs released from various cellular sources identify their cellular targets and convey signals to recipient cells. Then, mechanisms of action applicable to key neurological conditions such as stroke, multiple sclerosis and neurodegenerative diseases are presented. Pathways that deserve attention in specific disease contexts are discussed. We subsequently showcase considerations about EV biodistribution and delineate genetic engineering strategies aiming at enhancing brain uptake and signalling. By sketching a broad view of EV-orchestrated brain plasticity and recovery, we finally define possible future clinical EV applications and propose necessary information to be provided ahead of clinical trials. Our goal is to provide a steppingstone that can be used to critically discuss EVs as next generation therapeutics for brain diseases.