Nanoparticle cluster depolymerizes and removes amyloid fibrils for Alzheimer?s disease treatment

Aberrant amyloid-beta (A beta) fibrillation is the key event in Alzheimer's disease (AD), the depolymerization and removal of which are being pursued with enthusiasm. Herein, a nanoparticle cluster is designed for amy-loid-matching based on point-to-point strategy to prevent amyloid fibrillation. After reaching AD nidus, this cluster decomposes into ultra-small nanoparticles, and exposes more binding sites in different types to match with A beta sequence via multivalent binding. Notably, AD microenvironment sensitive nucleophilic substitution reaction generates strong covalent linkage between nanoparticle and amyloid, which ensures high binding specificity/affinity. The strong binding event competitively reduces amyloid-amyloid inter-actions thereby disintegrating amyloid fibrils. Not only that, monomeric A beta after fibrils depolymerization and nanoparticles reassemble into nanoparticle A beta composite. Such composite realizes A beta receptor mediated precise rapamycin delivery into microglia, further normalizing microglial immunologic dys-function for A beta removal and brain-friendly environment. This system interferes with amyloid fate, rescues memory deficits in AD. (c) 2023 Elsevier Ltd. All rights reserved.