Legumain-induced intracerebrally crosslinked vesicles for suppressing efflux transport of Alzheimer's disease multi-drug nanosystem

Brain barrier is both a protective permeability hurdle and a limitation site where therapeutic agents are excluded to enter the target region. Designing drug vehicle to overcome this notorious barrier bottle is challenging. Herein, we construct a stimuli-responsive self-assembled nanovesicle that delivers water-soluble drugs to prevent the efflux transport of brain barriers by responding to the endogenously occurring signals in Alzheimer's disease (AD) brain microenvironment. Once stimuli-responsive vesicles are accumulated in intracerebrally, the intrinsically occurring legumain endopeptidase cleaves the Ac-Ala-Ala-Asn-Cys-Asp (AK) short peptide on the drug vesicles to expose the 1,2 thiol amino group to cyclize with the cyano groups on 2-cyano-6-aminobenzothiazole (CABT) of the chaperone vesicles, thus triggering the formation of cross-linked micrometre-scale vesicles. Such a structural alteration completely prevents further brain barriers efflux. The superior neuroprotective capacity of cross-linked vesicles is validated in senescence accelerated mouse prone 8 (SAMP8). This smart multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment and can be adapted for the therapy of other central nervous system (CNS) disorders.