http://mooiparijs.nl/87em04t68i89.owenia With increasing life expectancy, brain-related diseases have become a major health problem globally. Two clearly differentiated routes, namely passive diffusion (i.e. lipophilic pathway) and active transport (mainly, adsorptive- or receptor-mediated transcytosis, AMT and RMT, respectively), are the most suitable approaches for drug delivery to the brain. The former is conveniently used for small cargos, while the latter enables the delivery of large therapeutics, such as proteins and nanoparticles (NPs). Compounds that are lipophilic, neutral or uncharged at pH 7.4 and have less than 8 hydrogen bonding groups are more suitable to cross the BBB. Low-density lipoprotein receptor-related protein-1 (LRP-1) is highly expressed in brain endothelial cells as well as brain tumour cells, neurons and astrocytes; it is also expressed in the lung, ovary, uterus and liver. The nicotinic acetylcholine receptor (nAChR) is widely expressed in the brain, including the endothelial cells of brain capillaries. The human transferrin receptor (TfR), highly expressed in brain capillaries, mediates the delivery of iron to the brain. TfR is also expressed in choroid plexus epithelial cells and neurons.