Multimeric Interacting Interface of Biologically Synthesized Zinc Oxide Nanoparticle Corona Efficiently Sequesters α-synuclein Against the Protein Fibrillation

Abstract

Alpha-Synuclein (αS) is an intrinsically disordered protein with the potential to form cross-β-sheet-rich insoluble amyloid fibrils linked to synucleinopathies. Small molecules like polyphenols and flavonoids have been explored to mitigate the aggregation of αS but failed in vivo due to poor bioavailability. To counter this problem, there is a need for a platform that concomitantly enhances the bioavailability of the mitigators and efficiently sequesters αS monomers against amyloidosis. Here, we demonstrate the sequestering potential of different surface-modified zinc oxide nanoparticles (ZnONPs) using in silico and biophysical approaches. The nano-interfaces of green-synthesized ZnONP more efficiently sequester αS in its native conformation and form amorphous aggregate-like structures, termed as flocs, than tyrosine-coated and bare ZnONP interfaces revealed by Intrinsic Fluorescence, Circular Dichroism (CD), Thioflavin T kinetics (ThT), and Transmission Electron Microscopy (TEM) data. GC-MS-based analysis of the bio-nano corona highlighted the rationale for efficient sequestering of αS monomers by the green-synthesized zinc oxide nanoparticle. The non-toxic nature of flocs was further confirmed by cytotoxicity, Reactive Oxygen Species (ROS), and Annexin/PI assays. Thus, the work exemplifies the multimeric interacting interface as a platform to efficiently sequester the protein and simultaneously enhance the bioavailability of the phytochemicals.