Stepwise Coordination-Driven Metal–Phenolic Nanoparticle as a Neuroprotection Enhancer for Alzheimer’s Disease Therapy

Current therapeutic strategies for Alzheimer’s disease (AD) mainly focus on inhibition of aberrant amyloid-β peptide (Aβ) aggregation. However, these strategies cannot repair the side symptoms (e.g., high neuronal oxidative stress) triggered by Aβ accumulation and thus show limited effects on suppressing Aβ-induced neuronal apoptosis. Herein, we develop a stepwise metal–phenolic coordination approach for the rational design of a neuroprotection enhancer, K8@Fe–Rh/Pda NPs, in which rhein and polydopamine are effectively coupled to enhance the treatment of AD in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. We discover that the polydopamine inhibits the aggregation of Aβ oligomers, and rhein helps repair damage to neurons triggered by Aβ aggregation. Based on molecular docking, we demonstrate that the polydopamine has a strong interaction with Aβ monomers/fibrils through its multiple recognition sites (e.g., catechol groups, imine groups, and indolic/catecholic π-systems), thereby reducing Aβ burden. Further investigation of the antioxidant mechanisms suggests that K8@Fe–Rh/Pda NPs promote the mitochondrial biogenesis via activating the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway. This finally inhibits neuronal apoptosis. Moreover, an intravenous injection of these nanoparticles potently improves the cognitive function in APP/PS1 mice without adverse effects. Overall, our work provides a promising approach to develop advanced nanomaterials for multi-target treatment of AD.