Serum albumin-embedding copper nanoclusters inhibit Alzheimer's β-amyloid fibrillogenesis and neuroinflammation.

Increasing evidence suggests that the accumulations of reactive oxygen species (ROS), β-amyloid (Aβ), and neuroinflammation are crucial pathological hallmarks for the onset of Alzheimer's disease (AD), yet there are few effective treatment strategies. Therefore, design of nanomaterials capable of simultaneously elimination of ROS and inhibition of Aβ aggregation and neuroinflammation is urgently needed for AD treatment. Herein, we designed human serum albumin (HSA)-embedded ultrasmall copper nanoclusters (CuNCs@HSA) via an HSA-mediated fabrication strategy. The as-prepared CuNCs@HSA exhibited outstanding multiple enzyme-like properties, including superoxide dismutase (>5000 U/mg), catalase, and glutathione peroxidase activities as well as hydroxyl radicals scavenging ability. Besides, CuNCs@HSA prominently inhibited Aβ fibrillization, and its inhibitory potency was 2.5-fold higher than native HSA. Moreover, CuNCs@HSA could significantly increase the viability of Aβ-treated cells from 60 % to over 96 % at 40 μg/mL and mitigate Aβ-induced oxidative stresses. The secretion of neuroinflammatory cytokines by lipopolysaccharide-induced BV-2 cells, including tumor necrosis factor-α and interleukin-6, was alleviated by CuNCs@HSA. In vivo studies manifested that CuNCs@HSA effectively suppressed the formation of plaques in transgenic C. elegans, reduced ROS levels, and extended C. elegans lifespan by 5 d. This work, using HSA as a template to mediate the fabrication of copper nanoclusters with robust ROS scavenging capability, exhibited promising potentials in inhibiting Aβ aggregation and neuroinflammation for AD treatment.