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Multifunctional Supramolecular Vesicles as Zn2+ -Triggered Microglial Modulator Alleviates Alzheimer's Disease
Zhi Jia1, Ran Tang1, Xiaoyu Yuan1
1Department of Chemistry, College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
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.
Insights
This study developed smart resveratrol-loaded vesicles that chelate zinc ions, reducing amyloid-beta aggregation and neuroinflammation. These vesicles reprogram microglia, offering a novel therapeutic strategy for Alzheimer's disease (AD) and other CNS disorders.
Area of Science:
- Neuroscience
- Biomedical Engineering
- Pharmacology
Background:
- Alzheimer's disease (AD) is characterized by zinc-induced amyloid-beta (Aβ) aggregation and microglia activation.
- Targeting excessive intracephalic zinc is a potential therapeutic strategy for AD.
- Simple zinc inhibition is insufficient to repair microglial damage.
Purpose of the Study:
- To construct intelligent resveratrol-loaded supramolecular vesicles (RES-loaded vesicles) with zinc ion chelation and responsive release capabilities.
- To alleviate Aβ fibrillation, oxidative stress, and microglial dysfunction in Alzheimer's disease models.
Main Methods:
- Developed resveratrol-loaded vesicles with zinc-chelating and responsive release functions.
- Encapsulation efficiency: 49.67%, Drug loading efficiency: 7.87%.
- Evaluated in vitro Aβ aggregation, microglia polarization, and cytotoxicity; assessed in vivo efficacy in AD mouse models via stereotactic and intranasal administration.
Main Results:
- RES-loaded vesicles modulated zinc-dependent Aβ aggregation.
- Vesicle cargo release in a zinc environment reprogrammed microglia from M1 to M2 phenotype.
- Reduced cytotoxicity from 29% to 12% and alleviated neuronal apoptosis, neuroinflammation, and cognitive impairment in AD mouse models.
Conclusions:
- Constructed intelligent RES-loaded vesicles effectively target zinc in the brain.
- Reprogramming microglia and reducing neuroinflammation offers a promising therapeutic approach for AD.
- This strategy provides a novel perspective for treating CNS disorders by leveraging zinc modulation.
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