Multifunctional Supramolecular Vesicles as Zn²⁺‐Triggered Microglial Modulator Alleviates Alzheimer's Disease

Abstract Zn²⁺‐induced β‐amyloid protein (Aβ) aggregation and microglia activation are the predominant contributors in Alzheimer's disease (AD). Regulating intracephalic excessive Zn²⁺ is a promising therapeutic strategy for AD treatment. However, only inhibition of Zn²⁺ is hardly to repair continuous damages caused by activated microglia. Herein, an intelligent resveratrol‐loaded supramolecular vesicles (RES‐loaded vesicles) with zinc ion chelation function and responsive release capability are constructed to alleviate Aβ fibrillation, oxidative stress, and microglial dysfunction. The resveratrol encapsulation efficiency and drug loading efficiency are calculated to be 49.67% and 7.87%, respectively. In vitro studies demonstrate that the RES‐loaded vesicles can modulate Zn²⁺‐dependent Aβ aggregation. More importantly, the cargoes will be released in zinc environment and further reprograms microglia from proinflammatory M1 phenotype toward anti‐inflammatory M2 phenotype, which prevents spontaneous neuroinflammation and alleviates cytotoxicity of cultured cells from 29% to 12%. With the stereotactic or intranasal administration, RES‐loaded vesicles can overcome the blood brain barrier, alleviate neuronal apoptosis, neuroinflammation, and ultimately ameliorate cognitive impairment in two AD mouse models. This work provides a new sight for taking advantage of Zn²⁺ to treat CNS disorders.