Protein engineering approaches for regulating blood-brain barrier transcytosis

The blood brain barrier (BBB) presents a challenge for the delivery of brain therapeutics. Trans-BBB delivery methods that use targeting vectors to coopt the vesicle trafficking machinery of BBB endothelial cells have been developed, but these are often hampered by limited flux through the BBB. A solution to this problem lies in the semi-rational engineering of BBB targeting vectors. Leveraging knowledge of intracellular trafficking, researchers have begun to tune selected binding properties of the vector-receptor interaction. Engineered binding affinity, avidity and pH-sensitivity have been shown to affect binding, intracellular sorting and release, ultimately leading to increased brain uptake of the targeting vector and its associated cargo. However, each targeted receptor may exhibit differential responses to engineered binding properties, illustrating the need to better understand vector-receptor interactions and trafficking dynamics.