Ceria-nanocluster based therapy for Alzheimer's disease through the modulation of activated microglia and attenuation of amyloid-β deposition.

Despite extensive efforts dedicated to developing therapies for Alzheimer's disease (AD), we still lack effective approaches capable of curing or halting its progression. Mounting evidence highlights the critical roles of dysfunctional microglia, which promote the abnormal accumulation of harmful protein deposits and initiate aggressive neuroinflammation, contributing to both the onset and advancement of AD. Hereby, we develop a brain-targeted ceria nanoparticle (T-CeNP) that exhibits both superoxide dismutase and catalase mimicking activities, for AD therapy. The functionalization of advanced glycation endproducts (RAGE) targeting peptide facilitates the blood-brain barrier (BBB) penetration of T-CeNP, prevents the formation of Aβ fibrils, and boosts Aβ degradation by microglia. By integrating the multifunctional RAGE-targeting ligand and bioactive CeNPs, T-CeNP can effectively cross the BBB, quench elevated reactive oxygen species, attenuate microglial activation, disrupt Aβ aggregation, and promote its clearance in an AD mouse model, thereby slowing the progression of AD.