Revisiting nanoparticle technology for blood-brain barrier transport: Unfolding at the endothelial gate improves the fate of transferrin receptor-targeted liposomes

Sorting of transferrin receptor-targeted liposomes in brain endothelial cells denoting the blood-brain barrier (BBB). These targeted liposomes undergo degradation or facilitated transport through the BBB. (a-b) TfR-targeted liposomes are initially endocytosed into clathrin-coated vesicles inside the BCEC. After the uptake, the liposomes are sorted into early endosomes (c) that mature into late endosomes and lysosomes, where it will be targeted for degradation (d). Uptake can also be followed by direct transcytosis of liposomes (e) or cargo liberation inside the endosome (f), both resulting in release on the abluminal side of the BCEC. (g) The endosomal sorting can theoretically also be guided towards re-packaging in the Golgi apparatus for abluminal secretion.100