Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB), a key border separating the general blood circulation from the brain parenchyma (Badaut et al. Fluids & Barriers of the CNS, 2024). We have developed novel BBB transport vehicles comprising engineered Fc fragments that exploit transcytotic pathways across brain endothelial cells for the CNS delivery of biotherapeutics. These transport vehicles have been engineered using directed evolution to bind either the apical domain of the human transferrin receptor (TfR; Kariolis et al. Science Translational Medicine, 2020) or CD98 heavy chain (Chew et al. Nature Communications, 2023), two highly expressed brain endothelial cell targets. My talk will present results demonstrating how the transport vehicle platform may be paired with a variety of different payloads (e.g. antibodies, enzymes, and antisense oligonucleotides) for increased brain exposures and therapeutic effects in animal models and in human beings. I will also discuss new data demonstrating that healthy neonatal mice exhibit higher vascular TfR expression and TfR-targeted transport vehicle brain exposure than observed in adult mice, whereas BBB transport capacity remains stable across adulthood. Elevated TfR-mediated brain delivery observed in early mouse development suggests the potential of added efficacy in utilizing TfR platforms for the treatment of early childhood diseases, e.g. brain-penetrant enzyme replacement therapies currently being evaluated for certain lysosomal storage disorders (Ullman et al. Science Translational Medicine, 2020; Arguello et al. Journal of Experimental Medicine, 2022). Overall, our work suggests this modular platform approach has great potential for the CNS delivery of multiple protein therapeutics covering a range of neurological disorders including Alzheimer’s disease, brain cancers, and neuronopathic mucopolysaccharidoses.