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.

(Self) assembled news: recent highlights from the supramolecular chemistry literature (Quarter 1, 2023)

“…After loading and dosing the vesicle within mouse models, they found that fibril aggregation had decreased and that the neuroinflammation pathway in the brain had not been turned on. Most importantly, they were able to rescue memory deficits in mouse models [3].…”

Linking Nitrogen-Rich Pillar[5]arene to Hyper-Cross-Linked Polymers for Efficient and Simultaneous Capture of Iodine and Methyl Iodide

“…Among them, pillar­[ n ]­arenes (P­[ n ]­A) are a macrocyclic host with rigid pillars and π-electron-rich external walls/cavities. They are often functionalized on the rims or incorporated into materials to impart physicochemical properties − or significant functions, such as environmental remediation, − disease diagnosis, and luminescence detection. − …”

Combining Multifunctional Delivery System with Blood–Brain Barrier Reversible Opening Strategy for the Enhanced Treatment of Alzheimer's Disease

“…To date, various functional brain-target delivery systems based on suppressing A𝛽 aggregation and ameliorating neuromicroenvironment have been proposed for AD treatment. [11][12][13][14][15] For instance, Wang's group first reported a multifunctional nanoformulation by combination of nanodrug-, gene-, and stem-cell-based along with imaging guided for AD treatment which can eliminate A𝛽, raise cell survival, and promote neural regeneration. [16] In addition, Kim's group developed a nanovaccine containing lipid nanoparticles loaded with A𝛽 peptides and rapamycin to achieve multitarget treating AD which could overcome the limitations of single-target therapy.…”