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

Abstract 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.