Aβ-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aβ clearance

Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aβ-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aβ clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aβ). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aβ clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aβ-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.