Abstract: Simultaneously addressing Aβ₄₂ aggregation and oxidative stress within the Alzheimer's disease (AD) microenvironment has emerged as a promising therapeutic strategy for countering the complex pathogenesis of AD. In this study, we developed a multifunctional nanocomposite (GQDs@MPN) with reactive oxygen species scavenging properties. This nanocomposite consists of graphene quantum dots encapsulated within a metal-polyphenol network (GQDs@MPN) formed by physiological Co (II)-coordinated epigallocatechin gallate (EGCG). GQDs@MPN effectively modulates the AD microenvironment by inhibiting Aβ₄₂ amyloidosis, attenuating oxidative stress, and regulating microglial activity. In vivo experiments demonstrated that GQDs@MPN, capable of crossing the blood-brain barrier (BBB), significantly reduced Aβ₄₂ deposition in APP/PS1 mice. Additionally, GQDs@MPN could exert its anti-inflammatory function by scavenging intracellular ROS and regulating the transformation of microglia from M1 phenotype to M2 phenotype, thus alleviating neuroinflammation. The underlying molecular mechanism is the up-regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) to clear ROS and subsequently inhibit the nuclear factor κB (NF-κB) signaling pathway. GQDs@MPN also effectively alleviated cognitive impairment and exhibited favorable biocompatibility in APP/PS1 mice. These findings suggest that GQDs@MPN is a promising candidate for multi-targeted AD therapy. We propose that such multifunctional nanocomposites could offer new avenues for developing novel AD inhibitors.

Key words: Alzheimer's disease, Blood-brain barrier, Metal-phenolic network, Oxidative stress, Neuroinflammation