Figure 3.

The blood–brain barrier, theoretically a motorway for a melting-pot of EXOs. Five routes have been described for EXOs interacting with a receiving cell: (1) association with a protein G-coupled receptor on the cell surface, inducing a signaling cascade; (2) adhesion to the cell surface and fusion, releasing the EXOs content in the cytoplasm, which can lead to several types of events, including cell signaling; (3) macropinocytosis; (4) nonspecific/lipid raft; or (5) receptor-mediated transcytosis, leading to its entry into the cell through the endocytic pathway and its storage in the MVB. Then, three outcomes remain possible for EXOs: (i) degradation by lysosomes; (ii) signaling induction through a backfusion event in the MVB releasing its content in the cytoplasm; or (iii) trafficking from the MVB to the plasma membrane as neoformed ILVs in the receiving cell. It is worth noting that except in pathological models, under TNF-α treatment [50], EVs and EXOs have not been described to cross the BBB through the paracellular pathway. Abbreviations: AJs: Adherens Junctions; EC: Endothelial Cells; ESCRT: Endosomal Sorting Complexes Required for Transport; ILV: IntraLuminal Vesicles; JAMs: Junctional Adhesion Molecules; NVU: Neuro-Vascular Unit; SNARE: Soluble N-ethylmaleimide-sensitive-factor Attachment protein REceptor; TJs: Tight Junctions.