Zn2 -Responsive Palladium Nanoclusters Synergistically Manage Alzheimer's Disease Through Neuroprotection and Inhibition of Oxidative Stress

The current focus on inhibiting β-Amyloid (Aβ) aggregation has shown great limitations for the management of Alzheimer's disease (AD). Multi-target strategies that synergistically exert neuroprotective effects and alleviate oxidative stress are effective strategies to modulate the AD microenvironment. Herein, a novel Zn2+-responsive nano-drug delivery platform (NWP) is developed using palladium nanoclusters (Pd NCs) as carriers, loaded with nerve growth factor (NGF), capped by supramolecular nanovalves containing carboxyl pillars[5]arenes (WP5) for the treatment of AD. Pd NCs have both ·OH elimination and catalase activities to alleviate oxidative stress. The larger specific surface area could significantly improve the loading capacity of NGF. The supramolecular nanovalve constructed by WP5 achieves precise targeting and controlled release of NGF with Zn2+ responsiveness, thereby improving the utilization of loading drugs. In vitro and in vivo experiments demonstrates that NWP effectively scavenges reactive oxygen species (ROS), protects neuronal cells from oxidative damage and modulates microglial polarization (the pro-inflammatory M1-phenotype microglial transition to the anti-inflammatory M2-phenotype), thus reducing the release of pro-inflammatory factors and alleviating neuroinflammation. Furthermore, intracerebral injection of NWP significantly ameliorates the learning and memory deficits of AD model mice. Overall, this Zn2+-responsive multi-target therapy provides a new option for AD.