A Chemically Engineered Macrocyclic Peptide Shuttle Overcomes Blood‐Brain Barrier in Aging Brain

The blood-brain barrier (BBB) poses a major challenge for the delivery of therapeutics into the central nervous system. Receptor-mediated transcytosis (RMT) is a highly efficient strategy for delivering therapeutics across the BBB. However, the age-dependent downregulation of key endothelial receptors limits its efficacy in age-related disorders. This underscores the urgent need to develop age-adapted strategies to enhance BBB traversal. Here, we report the discovery of a neuron-targeting macrocyclic peptide shuttle that actively triggers caveolae-mediated transcytosis, a pathway potentiated in brain endothelial cells during aging, through chemically engineered cross-linking architectures with tuned lipophilicity. In vivo evaluations in aged murine models revealed that the perfluoroalkane-tethered macrocycle achieves superior BBB traversal efficiency over current state-of-the-art receptor-mediated BBB peptide shuttles, with high biosafety. Importantly, our findings establish that the perfluoroalkane-containing architecture confers an optimal balance between BBB permeability and nonspecific cytotoxicity. This macrocycle shuttle platform provides a dual-function delivery system for both efficient BBB traversal and neuron-targeting in the aging brain, showing promise as a therapeutic delivery strategy for age-related neurodegenerative diseases.