A blood-brain barrier crossing peptide

The development of non-invasive brain-targeting delivery approaches is very important for the treatment of diseases related to the central nervous system (CNS), and receptor-mediated transcytosis (RMT) holds advantages of better specificity and efficacy over others. However, successful examples of brain-targeting delivery systems based on RMT are still limited. Here we report a novel tetrapeptide, GFFY, which is capable of efficiently crossing the blood-brain barrier (BBB). The tetrapeptide is highly versatile in covalent labeling with a fluorescence dye, Cy5.5, and the resulting Cy5.5-GFFY can self-assemble into nanospheres. We demonstrate that the nanospheres can efficiently deliver Cy5.5 to the brain by a fold increase of approximate 2.43, which is comparable to Cy5 penetration of damaged BBB in traumatic brain injury (about 3.5-fold of increase). We also investigate the mechanism of efficient BBB penetration, that is, the nanospheres specifically bind to the insulin receptor (IR) overexpressed on the BBB and then cross the BBB by IR-mediated transcytosis. Amino acid sequence changes and specific receptor inhibitors both reduce the efficiency of self-assembling peptides in shuttling through the BBB. Due to its high efficiency to reach the brain, and versatility to covalently conjugate or physically co-assemble with other therapeutics, we envision the great promise of our developed self-assembling GFFY for the delivery of both small-molecule and macromolecular therapeutics to treat CNS diseases.