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Transcytosis across brain capillary endothelial cell (BCEC) layer enables brain delivery of therapeutic macromolecules and nanocarriers. Interplay of their own properties and the properties of BCEC transport targets or intracellular trafficking machinery affects brain uptake. This interplay becomes even more nuanced for macromolecules targeted to several proteins on BCEC, as well as for engineered nanoparticles and viral vectors with complex biological interactions that may involve multiple proteins on the surface and within BCEC. Unraveling the effects of this interplay is paramount to 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 BCEC, trafficking across BCEC, and availability in the bloodstream. It then highlights how interactions between large therapeutics and their BCEC surface targets, but also intracellular proteins, may be adjusted to minimize unproductive trafficking routes or entrapment, thereby maximizing transcytosis across BCEC. 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.