Allosteric Targeted Drug Delivery for Enhanced Blood-Brain Barrier Penetration via Mimicking Transmembrane Domain Interactions

Authors

Kaicheng Tang
Zhongjie Tang
Miaomiao Niu
Zuyin Kuang
Weiwei Xue
Xinyu Wang
Xinlong Liu
Yang Yu
Seongdong Jeong
Yifan Ma
Annette Wu
Betty Y S Kim
Wen Jiang
Zhaogang Yang
Chong Li

Publication Date

4-10-2025

Journal

Nature Communications

Abstract

Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin α

Keywords

Blood-Brain Barrier, Drug Delivery Systems, Humans, Animals, Ligands, Receptor, Insulin, Allosteric Regulation, Drug Carriers, Peptides, Mice

DOI

10.1038/s41467-025-58746-x

PMID

40210849

PMCID

PMC11986143

PubMedCentral® Posted Date

4-10-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes