Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain

Abstract Targeted protein degradation has emerged as a transformative therapeutic strategy, yet its application to neurodegenerative diseases remains fundamentally constrained by the blood-brain barrier (BBB) and lesion specificity. Critically, the BBB undergoes age-dependent functional remodeling, further exacerbating the difficulty of therapeutic intervention. Here we report BBB-permeable macrocyclic chimeras (BmTACs), a modular degradation platform for selective elimination of activated death-associated protein kinase 1 (DAPK1) in the aging brain. BmTACs harness a macrocyclic peptide shuttle that exploits age-upregulated caveolae-mediated transcytosis in brain endothelial cells to achieve efficient BBB traversal and neuron-targeting. A reactive oxygen species (ROS)-responsive caging group on the von Hippel-Lindau ligand enables conditional PROTAC activation exclusively within the high-ROS microenvironment of Alzheimer’s disease lesions, minimizing off-target degradation. Systemic administration of BmTACs in aged APP/PS1 mice achieved potent degradation of activated DAPK1, attenuated amyloid-β deposition and Tau hyperphosphorylation, and improved cognition. This work establishes a modular, senescence-adapted paradigm for targeted protein degradation in the aging central nervous system.