Fig. 7.

Mechanisms under exosome crossing through the BBB. Exosomes harboring transferrin can bind to the TFR at the surface of brain ECs. In the following step, exosomes are trapped inside the clathrin-coated pit and enter the cells. Clathrin-coated vesicles containing exosomes are transported by cytoskeletal actin filaments and directed to lysosomal or endosomal pathways. Exosomes are degraded throughout the lysosomal pathway inside the cytoplasm, and Fe is released. In the endosomal pathway, exosomes are transferred to the abluminal side of ECs, and TFR is recycled to the cell surface. Exosomes are the potential to pass BBB by recruiting the paracellular route. Under inflammatory and sometimes physiological conditions, exosomes cross BBB by downregulating the expression of TJs proteins and diminishing the TEER. TFR Transferrin receptor, ECs Endothelial cells, BBB Blood–brain barrier; TEER Trans-endothelial electrical resistance