Chemical design principles governing receptor-mediated blood-brain barrier transcytosis: analysis of 563 molecular shuttles.

Abstract

The blood-brain barrier (BBB) remains a major obstacle to central nervous system drug delivery. Receptor-mediated transcytosis offers a promising strategy, motivating diverse molecular shuttle designs. Here, we systematically analyse 563 chemically defined BBB shuttles, comprising peptides (229), aptamers (149), antibodies (114), nanobodies (11), primary nanoparticles (12), and other constructs (48). Despite extensive chemical diversity, documented advanced-stage evidence remains concentrated in relatively few constructs. In the originally annotated subset (356/563 shuttles), only 39 reached the level indicating quantitative in vivo brain exposure or functional CNS delivery. Antibodies accounted for 71.8% (28/39) of these records, compared with 28.2% (11/39) for peptides and aptamers combined. Transferrin receptor dominated aptamer targeting (71.8%), whereas neonatal Fc receptor predominated among peptides (73.4%). The 39 advanced-stage records represented only seven annotated receptor targets. These findings reveal a disconnect between molecular diversification and documented translational evidence for BBB shuttles in our dataset. Further progress requires rigorous quantification of brain delivery, improved mechanistic validation, and systematic optimisation of receptor engagement, trafficking, molecular design, and cargo release.

Abstract as supplied by the indexing source. © the authors / publisher.