Abstract
The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain. An increasing amount of data suggests that extracellular vesicles (EVs), i.e., membrane derived vesicles that inherently protect and transfer biological cargoes between cells, naturally cross the CNS barriers. Moreover, EVs can be engineered with targeting ligands to obtain enriched tissue targeting and delivery capacities. In this review, we provide a detailed overview of the literature describing a natural and engineered CNS targeting and therapeutic efficiency of different cell type derived EVs. Hereby, we specifically focus on peripheral administration routes in a broad range of CNS diseases. Furthermore, we underline the potential of research aimed at elucidating the vesicular transport mechanisms across the different CNS barriers. Finally, we elaborate on the practical considerations towards the application of EVs as a brain drug delivery system.
Highlights
The treatment of central nervous system (CNS) pathologies is severely hampered by the presence of tightly regulated CNS barriers that restrict drug delivery to the brain
The treatment of a broad range of central nervous system (CNS) pathologies is still severely hampered by the presence of multiple brain barriers [1,2]
The included studies report on the intrinsic brain targeting potential of specific extracellular vesicles (EVs), their brain barrier crossing capacity and their therapeutic effect in a broad range of CNS pathologies upon intravenous (IV), intraperitoneal (IP), subcutaneous (SC) or intranasal (IN) delivery
Summary
The treatment of a broad range of central nervous system (CNS) pathologies is still severely hampered by the presence of multiple brain barriers [1,2]. The included studies report on the intrinsic brain targeting potential of specific EVs, their brain barrier crossing capacity and their therapeutic effect in a broad range of CNS pathologies upon intravenous (IV), intraperitoneal (IP), subcutaneous (SC) or intranasal (IN) delivery. Tables are included that contain more details on the study methodology and we indicated which read-outs for brain targeting (i.e., biodistribution, cargo delivery and/or a therapeutic read-out) were used. The latter are important considerations as the presence of a (labelled) EV in the brain does not necessarily mean that the EV will successfully deliver its content whereas a sole therapeutic read-out only indirectly suggests brain delivery.
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