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

The fibrillation of amyloid-ß (Aß) is the critical causal factor in Alzheimer's disease (AD), the dissolution and clearance of which are promising for AD therapy. Although many Aß inhibitors are developed, their low Aß-binding affinity results in unsatisfactory effect. To solve this challenge, the Aß sequence-matching strategy is proposed to tail-design dissociable nanosystem (B6-PNi NPs). Herein, B6-PNi NPs aim to improve Aß-binding affinity for effective dissolution of amyloid fibrils, as well as to interfere with the in vivo fate of amyloid for Aß clearance. Results show that B6-PNi NPs decompose into small nanostructures and expose Aß-binding sites in response to AD microenvironment, and then capture Aß via multiple interactions, including covalent linkage formed by nucleophilic substitution reaction. Such high Aß-binding affinity disassembles Aß fibrils into Aß monomers, and induces the reassembly of Aß&nanostructure composite, thereby promoting microglial Aß phogocytosis/clearance via Aß receptor-mediated endocytosis. After B6-PNi NPs treatment, the Aß burden, neuroinflammation and cognitive impairments are relieved in AD transgenic mice. This work provides the Aß sequence-matching strategy for Aß inhibitor design in AD treatment, showing meaningful insight in biomedicine.