Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions.

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 as model targets, respectively, and can effectively overcome pseudotargets or target loss caused by shedding or mutating the extracellular domain of target receptors. Moreover, these ligands can be spontaneously embedded in the phospholipid layer of lipid carriers using a plug-and-play approach without chemical modification, with excellent tunability and immunocompatibility. Overall, this allosteric targeted drug delivery strategy can be applied to multiple receptor targets and drug carriers and offers promising therapeutic benefits in brain diseases.