A tailor-designed dissociable nanosystem can decompose into small nanostructures in brain microenvironment of Alzheimer’s disease, and then recognize and bind amyloid-β for the dissolution, reassembly and further clearance of amyloid-β fibrils. This nanosystem rescues cognitive and memory impairments in mice for Alzheimer’s disease therapy.
The fibrillation of amyloid-β (Aβ) is the critical causal factor in Alzheimer’s disease (AD), the dissolution and clearance of which are promising for AD therapy. Although many Aβ inhibitors are developed, their low Aβ-binding affinity results in unsatisfactory effect. To solve this challenge, the Aβ sequence-matching strategy is proposed to tail-design dissociable nanosystem (B6-PNi NPs). Herein, B6-PNi NPs aim to improve Aβ-binding affinity for effective dissolution of amyloid fibrils, as well as to interfere with the in vivo fate of amyloid for Aβ clearance. Results show that B6-PNi NPs decompose into small nanostructures and expose Aβ-binding sites in response to AD microenvironment, and then capture Aβ via multiple interactions, including covalent linkage formed by nucleophilic substitution reaction. Such high Aβ-binding affinity disassembles Aβ fibrils into Aβ monomers, and induces the reassembly of Aβ&nanostructure composite, thereby promoting microglial Aβ phogocytosis/clearance via Aβ receptor-mediated endocytosis. After B6-PNi NPs treatment, the Aβ burden, neuroinflammation and cognitive impairments are relieved in AD transgenic mice. This work provides the Aβ sequence-matching strategy for Aβ inhibitor design in AD treatment, showing meaningful insight in biomedicine.
Qianhua Feng, Xueli Zhang, Nan Zhang, Huan Gu, Ning Wang, Jing Chen, Xiaomin Yuan, Lei Wang*
How to cite:
Q. Feng, X. Zhang, N. Zhang, H. Gu, N. Wang, J. Chen, X. Yuan, L. Wang, Exploration 2023, 20230048.