Multiple effects of polydopamine nanoparticles on Cu2+-mediated Alzheimer's β-amyloid aggregation

• PDA NPs change Cu 2+ -mediated Aβ aggregation pathway by chelating Cu 2+. • PDA NPs remove ROS and rescue damaged cells. • NIR photothermal effect of PDA NPs promotes degrading Aβ 42 -Cu 2+ complexes. • PDA NPs reduce Aβ plaques and prolong the lifespan of AD nematodes. Deposition of β-amyloid protein (Aβ) is the main hallmark of Alzheimer's disease (AD), and it has been well recognized that Cu 2+ -mediated Aβ aggregation plays a crucial role in AD pathological processes. Cu 2+ binding to Aβ can promote the production of reactive oxygen species (ROS) through Fenton-like reactions and produce more toxic Aβ-Cu 2+ species under Cu 2+ stimulation. Thus, the development of nanomaterials that can inhibit Cu 2+ -mediated Aβ aggregation and degrade Aβ-Cu 2+ complexes is considered an effective strategy for the prevention and treatment of AD. In this study, polydopamine nanoparticles (PDA NPs) were prepared and the results reveal that PDA NPs potently inhibit Cu 2+ -mediated Aβ aggregation and effectively reduce the formation of Aβ-Cu 2+ complexes. In vitro experiments show that PDA NPs efficiently eliminate ROS generation catalyzed by Cu 2+ or Aβ-Cu 2+ complexes, thus rescuing cultured cells by reducing intracellular ROS levels. More importantly, PDA NPs can depolymerize Aβ-Cu 2+ complexes, and the degradation of Aβ-Cu 2+ complexes is promoted by near-infrared light irradiation due to their high photothermal conversion ability. In vivo studies reveal that PDA NPs significantly reduce the deposition of Aβ plaques in the presence of Cu 2+ and extend the lifespan of AD nematodes from 11 to 14 d. Thus, the PDA NPs developed herein are multifunctional against Cu 2+ -mediated Aβ aggregation for the potential prevention and treatment of AD.