Ligand-Engineered Nanoplatforms for Receptor-Mediated Drug Delivery Across the Blood–Brain Barrier: Design Principles and Translational Considerations

The blood–brain barrier (BBB) excludes most therapeutic agents from the central nervous system and remains a major constraint in the treatment of glioblastoma, Alzheimer’s disease, and other neurological disorders. Receptor-mediated transcytosis (RMT) offers a non-invasive route in which ligand-functionalized carriers engage receptors on brain endothelial cells and undergo vesicular transport across the BBB. This review examines transferrin (Tf), apolipoprotein E (ApoE), and receptor-binding peptides as the principal ligand classes used to engineer BBB-penetrating nanoplatforms, including polymeric nanoparticles, liposomes, micelles, lipid nanoparticles, and biomimetic carriers. Unlike reviews organized primarily by carrier type, administration route, or disease indication, we use a ligand-centered framework to connect receptor selection with affinity and avidity, surface density and orientation, intracellular trafficking, and carrier architecture. Particular attention is given to the progression from full-length natural proteins to compact peptides and stability-engineered ligands, including retro-inverso, stapled, and stimulus-cleavable designs. We also summarize representative within-study improvements in brain delivery and therapeutic outcome while emphasizing that effect sizes depend on the BBB model, disease model, dosing regimen, comparator, and analytical endpoint. Finally, we discuss species specificity, receptor-mediated safety liabilities, conjugation reproducibility, scale-up, and human-relevant BBB evaluation. These considerations position ligand engineering and pharmaceutical manufacturability as interdependent requirements for translating RMT nanoplatforms into clinically viable CNS drug-delivery systems.