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

Aberrant amyloid-β (Aβ) 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 amyloid-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 Aβ 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 interactions thereby disintegrating amyloid fibrils. Not only that, monomeric Aβ after fibrils depolymerization and nanoparticles reassemble into nanoparticle&Aβ composite. Such composite realizes Aβ receptor mediated precise rapamycin delivery into microglia, further normalizing microglial immunologic dysfunction for Aβ removal and brain-friendly environment. This system interferes with amyloid fate, rescues memory deficits in AD.