Differential effects of silver and iron oxide nanoparticles on IAPP amyloid aggregation

Recent studies have shown promise on the use of small molecules and nanoparticles (NPs) for the inhibition of protein aggregation, a hallmark of neurodegenerative diseases and type 2 diabetes (T2D). Towards this end here we show the differential effects of silver and iron oxide nanoparticles (AgNPs and IONPs) on the mesoscopic properties of human islet amyloid polypeptide (IAPP) aggregation associated with T2D. Both citrate- and branched polyethyleneimine-coated AgNPs (c-AgNPs, bPEI-AgNPs) inhibited IAPP aggregation at 500 μg mL^-1, likely through electrostatic attraction and sequestering of IAPP monomers from fibrillation. In comparison, bare, brushed polyethylene glycol- and phosphorylcholine-grafted IONPs (bPEG-IONPs, bPC-IONPs) at 500 μg mL^-1 elicited no major effect on IAPP fibril contour length, while bPC-IONPs induced significant fibril softening and looping likely mediated by dipolar interactions. While monovalent Ag⁺ up to 50 μg mL^-1 showed no effect on the contour length or stiffness of IAPP fibrils, multivalent Fe³⁺ at 5 μg mL^-1 halted IAPP fibrillation likely through ion-peptide crosslinking. Except bPEI-AgNPs, all three types of IONPs and c-AgNPs at 100 μg mL^-1 alleviated IAPP toxicity in HEK293 cells indicating no clear correlation between protein aggregation and their induced cytotoxicity. This study demonstrates the complexity of protein aggregation intervened by NPs of different physicochemical properties and-together with existing literature-facilitates nanotechnological applications for mitigating amyloid-mediated pathologies.