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Receptor\u2010mediated transcytosis (RMT) is a highly efficient strategy for delivering therapeutics across the BBB. However, the age\u2010dependent downregulation of key endothelial receptors limits its efficacy in age\u2010related disorders. This underscores the urgent need to develop age\u2010adapted strategies to enhance BBB traversal. Here, we report the discovery of a neuron\u2010targeting macrocyclic peptide shuttle that actively triggers caveolae\u2010mediated transcytosis, a pathway potentiated in brain endothelial cells during aging, through chemically engineered cross\u2010linking architectures with tuned lipophilicity. In vivo evaluations in aged murine models revealed that the perfluoroalkane\u2010tethered macrocycle achieves superior BBB traversal efficiency over current state\u2010of\u2010the\u2010art receptor\u2010mediated BBB peptide shuttles, with high biosafety. Importantly, our findings establish that the perfluoroalkane\u2010containing architecture confers an optimal balance between BBB permeability and nonspecific cytotoxicity. This macrocycle shuttle platform provides a dual\u2010function delivery system for both efficient BBB traversal and neuron\u2010targeting in the aging brain, showing promise as a therapeutic delivery strategy for age\u2010related neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/anie.202520279","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T06:27:56Z","timestamp":1764052076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Chemically Engineered Macrocyclic Peptide Shuttle Overcomes Blood\u2010Brain Barrier in Aging Brain"],"prefix":"10.1002","volume":"65","author":[{"given":"Licong","family":"Peng","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering College of Medicine Southwest Jiaotong University  Chengdu Sichuan 610031 P. R. 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