Physiological strategies for brain delivery

The blood-brain barrier (BBB) remains an obstacle to treat neurological diseases, prompting the development of delivery strategies to target therapies to the brain. Receptor-mediated transport has become a major focus of research efforts aiming to exploit innate transport mechanisms. The last decade has seen important innovations ranging from ligand-modified nanocarriers to engineered biologics that harness trafficking pathways. However, such developments have demonstrated brain delivery requires a nuanced engagement of target proteins to ensure efficient internalization and intracellular trafficking. Therefore, much remains to be understood of BBB transport mechanisms to ensure maximal brain delivery of therapeutics. Furthermore, accumulating evidence indicates cell-membrane targets do not necessarily require an innate biological transport function to promote transport across the BBB. These observations open the possibility of expanding our target repertoire beyond transport-related proteins. Novel targets may therefore include structural or signalling proteins which have a more favourable brain-to-periphery expression ratio. In addition, they may include non-protein components of the cell membrane, for instance the glycocalyx covering endothelial surfaces. Such novel targets would therefore allow us to harness more fully the phenotypic specialization of brain endothelial cells. In addition, recent years have witnessed the development of targeting strategies harnessing not only structural differences of brain endothelial cells, but in addition take advantage of the dynamic control of BBB specialization. As such, advances have been made to exploit cell-membrane dynamics; haemodynamic response; vascular segmentation; or pathological modulation. The field of brain delivery is therefore advancing towards exploiting the highly unique physiology of the BBB to achieve a more dynamic approach to BBB targeting and maximize transport into the brain.