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

Area of Science:

• Neuroscience
• Biotechnology
• Drug Delivery

Background:

• The blood-brain barrier (BBB) restricts therapeutic entry into the central nervous system.
• Receptor-mediated transcytosis (RMT) is effective for BBB drug delivery but declines with age.
• Age-related decline in BBB receptor function necessitates new therapeutic delivery strategies.

Purpose of the Study:

• To develop an age-adapted strategy for enhanced therapeutic delivery across the BBB.
• To discover a novel neuron-targeting shuttle that utilizes age-potentiated transcytosis pathways.
• To create a safe and efficient platform for treating age-related neurological disorders.

Main Methods:

• Engineered a macrocyclic peptide shuttle with specific cross-linking architectures and tuned lipophilicity.
• Investigated caveolae-mediated transcytosis, a pathway enhanced in aged brain endothelial cells.
• Evaluated shuttle efficacy and biosafety in aged murine models.

Main Results:

• The perfluoroalkane-tethered macrocycle demonstrated superior BBB traversal efficiency compared to existing RMT shuttles.
• The shuttle successfully triggered caveolae-mediated transcytosis, bypassing age-dependent receptor downregulation.
• The macrocycle architecture achieved an optimal balance between BBB permeability and low cytotoxicity.

Conclusions:

• The developed macrocycle peptide shuttle platform offers efficient BBB traversal and neuron-targeting in the aging brain.
• This approach shows significant promise for therapeutic delivery in age-related neurodegenerative diseases.
• The study highlights the potential of targeting age-enhanced pathways for improved drug delivery.