Develop potential multi-target drugs by self-assembly of quercetin with amino acids and metal ion to achieve significant efficacy in anti-Alzheimer’s disease

Exploring multi-target drugs (MTDs) is a prevalent method against Alzheimer’s disease (AD). However, the current developed MTDs based on the “framework combination” technique or using flavonoids have not realized better healing effects owing to a complex metabolic process and low bioavailability. Here, we propose an alternative strategy to develop self-assembled nanoparticles (NPs) as MTDs using 9-fluorenylmethyloxycarbonyl-tryptophan (Fmoc-Trp), quercetin (Que), and Fe²⁺ as building blocks through coordination and electrostatic interaction to generate Fmoc-Trp-Fe²⁺-Que (FTFQ) NPs. Whether in cell or in vivo, FTFQ NPs exhibited considerable biocompatibility attributing to the inherent biological affinity of assembly units. By combining the advantages of assemble approach and nanostructures, the obtained FTFQ NPs greatly enhanced the bioavailability of Que and displayed synergistic therapeutic effects through reducing Aβ aggregation in direct/indirect means and eliminating the toxicity induced by ROS and Aβ oligomer/fibrils. Furthermore, FTFQ NPs could obviously restore the AD zebrafish’s mobility and stimulus response ability. More importantly, developing self-assembly NPs as MTDs could be an efficient and general method to promote other novel MTDs by extending the assemble units to other drugs, peptides, and metal ions. Based on above benefits, these self-assembled NPs could be as potential MTDs and show great promising application in AD treatment.