This opinion reviews transcytosis and therapeutic engagement in brain parenchyma, suggesting strategies to enhance retention.
Transcytosis across the blood-brain barrier (BBB) enables systemically administered large therapeutics to reach the brain parenchyma, but their fate in the parenchyma ultimately governs their therapeutic effect. Recent studies show that brain parenchymal cell uptake, internalization kinetics, reuptake at the BBB, and diffusion in the brain parenchyma shape the distribution and retention of therapeutics. Target engagement further influences their behavior beyond the BBB. These insights have prompted new strategies to enhance their distribution, retention, and target engagement. These include the selection of transport targets with favorable trafficking properties, the use of anchoring proteins, and modeling-based optimization. This opinion highlights emerging understanding of the fate of therapeutics in the brain parenchyma and outlines strategies to optimize this fate.
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Habib Baghirov (2025) studied this question.
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