A Metal-Peptide Framework as a Nanozyme for the Attenuation of Amyloid-β Aggregation and Reactive Oxygen Species

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by abnormal performance in memory, cognition, and language, and it imposes a heavy economic burden worldwide. Amyloidosis and oxidative stress are highly associated with AD progression, yet limited clinical drugs are available at present. Nanozymes exhibit diverse enzyme-mimetic activities and have attracted widespread attention as a promising alternative candidate for scavenging reactive oxygen species to maintain the oxidation-antioxidation balance in cells. Neurotoxic amyloid-β (Aβ) aggregation is also a critical event in AD pathology. The development of dual-targeting nanomaterials with antiamyloidosis ability and enzyme-mimicking activity is expected to be a promising strategy for the treatment of amyloidosis and reactive oxygen species-mediated AD progression. Here, bimetallic-peptide framework nanozymes (CuZn-PEP NZs) with amyloid-β (Aβ) attenuating ability, multiple enzyme-mimicking properties, and broad-spectrum reactive oxygen species scavenging capacity were endowed to inhibit Aβ fibrillization, disaggregate Aβ fibrils, and scavenge Aβ fibril-induced reactive oxygen species. An obvious inhibitory effect on Aβ fibrillization and a disaggregation effect on Aβ fibrils were observed after treatment with CuZn-PEP NZs. Meanwhile, the cytotoxicity of Aβ fibrils toward PC12 cells was significantly reduced by CuZn-PEP NZs. Meanwhile, CuZn-PEP NZs with multiple redox pairs exhibit superoxide dismutase, catalase, and glutathione peroxidase-mimicking enzyme properties simultaneously, which further display cytoprotective effects against Aβ fibril-induced reactive oxygen species and mitochondrial damage. Besides, cellular studies verified that CuZn-PEP NZs possess excellent biocompatibility and blood-brain barrier penetration capacity. Overall, these bimetallic-peptide framework nanozymes represent a promising perspective for attenuation of amyloid-β aggregation and reactive oxygen species simultaneously, which highlights the potential of nanozymes for the treatment of amyloidosis and reactive oxygen species-mediated AD progression.