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.

在这里，受超分子包合复合物概念的启发，我们成功地制造了基于二甲双胍 (Met) 的超分子纳米药物，该药物具有对 Aβ 响应的按需药物释放，用于通过增强小胶质细胞 Aβ 清除率来协同治疗阿尔茨海默病 (AD)。有趣的是，低剂量Met（1.1 mg/kg）的引入不仅可以显着提高纳米药物的结构稳定性，还可以与多奈哌齐（Don）发挥协同抗痴呆作用。此外，这种具有优异生理稳定性的纳米药物可以选择性地穿透血脑屏障（BBB），靶向大脑，增加小胶质细胞的有效摄取。和神经元，然后在过表达的淀粉样蛋白-β（Aβ）的刺激下实现同时时空的按需药物释放。此外，从纳米药物中释放的 Met 和 Don 通过溶酶体途径增强小胶质细胞的吞噬作用和 Aβ 清除，表现出优异的协同抗痴呆作用。总之，我们报告了一种基于 Aβ 响应性超分子纳米药物的 AD 治疗协同策略，有望为改善中枢神经系统疾病提供一种新的临床治疗思路。