Peptide-Modified Mo Polyoxometalate Nanoparticles Suppress Zn2+-Induced Aβ Aggregation

Graphical Peptide@POMs nanoparticles with Aβ-targeting peptides are used for Alzheimer's disease treatment in mice. First, synthetic peptide-modified Mo-POM nanoparticles are synthesized. Then, the assembled Peptide@POMs nanoparticles can effectively inhibit Zn 2+ -induced Aβ40 aggregation, penetrate the blood-brain barrier, and bind to Aβ. In addition, Peptide@POMs nanoparticles protect neurons from Aβ40-mediated neurotoxicity. The abnormal metabolism of amyloid-β (Aβ) peptide, as one of the main components of senile plaques, plays a vital role in the pathogenesis of Alzheimer's disease (AD). Our previous work showed that polyoxometalates (POMs) that inhibited the formation of Aβ aggregates were promising for AD therapy. Here, peptide-modified Mo polyoxometalate (Mo-POMs) nanoparticles were synthesized by the self-assembly of Aβ target peptide and Mo-POMs based on our previous work. Importantly, after modifying with the Aβ target peptide, the Mo polyoxometalate (Mo-POMs) nanoparticles exhibited enhanced blood-brain barrier (BBB) penetration and high binding affinity with Aβ species. The interactions between the Peptide@Mo-POMs nanoparticle and Aβ in the presence of Zn 2+ were comprehensively studied using physicochemical methods (spectroscopy, ThT fluorescence, turbidity tests). Peptide@Mo-POMs could suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn 2+ -induced Aβ aggregation. In addition, in vitro cell experiments revealed that Peptide@Mo-POMs could target and be well absorbed by PC12 cells, leading to the inhibition of intracellular Aβ aggregation and reduced Aβ aggregates-induced cytotoxicity. The blood-brain barrier (BBB) permeability of Peptide@Mo-POMs was also revealed by the Transwell experiment. This study gives a mechanistic understanding into how Peptide@Mo-POMs can work through a synergistic interaction with metal ions and Aβ, and provides new insights into the design and synthesis of POMs as Aβ inhibitors in the treatment of AD.