Abstract

Metal ion dysregulation is a critical pathological driver and a promising therapeutic target in Alzheimer's disease (AD). This study presents a novel multifunctional nanoplatform based on a covalent organic framework functionalized with 8-hydroxyquinoline (COF-HQ), engineered to simultaneously address the multifaceted pathology of AD. The material not only effectively chelates Cu2+ to inhibit and reverse Cu2+-induced amyloid-β (Aβ) aggregation but also, upon coordination, forms a complex with potent superoxide dismutase (SOD)-mimetic activity. This catalytic function enables the continuous scavenging of reactive oxygen species (ROS), thereby alleviating oxidative stress in the neuronal microenvironment. Furthermore, COF-HQ drives microglial polarization from the pro-inflammatory M1 to the anti-inflammatory M2 state and restores lysosomal acidification and function impaired by Aβ-Cu2+, thereby enhancing microglial phagocytosis and clearance of Aβ to break the vicious cycle of impaired degradation. The multivalent porous architecture of the COF scaffold provides enhanced binding capacity and stability, resulting in superior anti-aggregation, antioxidant, and cytoprotective efficacy compared to its molecular building block. In vivo studies demonstrate that systemic administration of COF-HQ significantly improves cognitive performance in behavioral tests, reduces cerebral Aβ plaque burden, and attenuates synaptic and neuronal loss in an AD mouse model. This work establishes a new COF-based therapeutic paradigm that concurrently targets metal dyshomeostasis, protein misfolding, oxidative stress, and defective cellular clearance, offering a comprehensive and integrated nanotherapeutic strategy for AD.