Strategies for Transcytosis-Based Delivery across the Blood-Brain Barrier

Transcytosis across brain microvascular endothelial cells (BMEC) enables brain delivery of biologics and nanocarriers. The interplay between their properties and those of BMEC transport targets or intracellular trafficking machinery affects brain uptake. This interplay becomes even more nuanced for macromolecules targeted to several proteins on BMEC, as well as for engineered nanoparticles and viral vectors with complex biological interactions that may involve multiple proteins on the surface and within BMEC. Unraveling the effects of this interplay is crucial for further improvements in delivery. This paper proposes a framework where the delivery of systemically administered large therapeutics across the blood-brain barrier is predicated on three components: availability on the surface of BMEC, trafficking across BMEC, and availability in the bloodstream. It then highlights how interactions between large therapeutics and their BMEC surface targets, but also intracellular proteins, may be adjusted to minimize unproductive trafficking routes or entrapment, thereby maximizing transcytosis across BMEC. Finally, it suggests strategies to increase the availability of large therapeutics in the bloodstream and outlines how these individual adjustments can be balanced to improve overall transport across the blood-brain barrier.