Extracellular vesicles: Novel promising delivery systems for therapy of brain diseases.

Extracellular vesicles (EVs) are cell-derived membrane vesicles virtually secreted by all cells, including brain cells. EVs are a major term that includes apoptotic bodies, microvesicles and exosomes. The release of EVs has been recognized as an important modulator in cross-talking between neurons, astrocytes, microglia and oligodendrocytes, not only in central nervous system (CNS) physiology but also in neurodegenerative and neuroinflammatory disease states as well as in brain tumors, such as glioma. EVs are able to cross the blood brain barrier (BBB), spread to body fluids and reach distant tissues. This prominent spreading ability has suggested that EVs can be exploited into several different clinical applications ranging from biomarkers to therapeutic carriers. Exosomes, the well-studied group of EVs, have been emerging as a promising tool for therapeutic delivery strategies due to their intrinsic features, such as the stability, biocompatibility and stealth capacity when circulating in bloodstream, the ability to overcome natural barriers and inherent targeting properties. Over the last years, it became apparent that EVs can be loaded with specific cargoes directly in isolated EVs or by modulation of producer cells. In addition, the engineering of its membrane for targeting purposes is expected to allow generating carriers with unprecedented abilities for delivery in specific organs or tissues. Nevertheless, some challenges remain regarding the loading and targeting of EVs for which more research is necessary, and will be discussed in this review. Recently-emerged promising derivations are also discussed, such as exosome associated with adeno-associated virus (AAV) vectors (vexosomes), enveloped protein nanocages (EPNs) and exosome-mimetic nanovesicles. This article provides an updated review of this fast-progressing field of EVs and their role in brain diseases, particularly focusing in their therapeutic applications.