Antibody Engineering for Receptor-Mediated Transcytosis Across the Blood-Brain Barrier.

Efficient delivery of therapeutic antibodies into the central nervous system (CNS) remains severely limited by the restrictive nature of the blood-brain barrier (BBB). Receptor-mediated transcytosis (RMT) has emerged as a promising strategy to enhance antibody transport across the BBB. In this Viewpoint, we highlight recent advances in RMT-based antibody delivery, focusing specifically on three representative BBB receptors: transferrin receptor (TfR), insulin receptor (InsR), and neonatal Fc receptor (FcRn). By comparing antibody engineering strategies that target these receptors, we summarize current progress, discuss critical limitations, and suggest directions for advancing CNS-targeted therapeutic antibodies. This Viewpoint provides valuable insights for selecting appropriate RMT targets and optimizing antibody-based therapies for CNS diseases.