The dissolution, reassembly and further clearance of amyloid‐β fibrils by tailor‐designed dissociable nanosystem for Alzheimer's disease therapy

Abstract 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.