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Zahra Zand,1,* Pegah Afarinesh Khaki,2,* Abbas Salihi,3,4 Majid Sharifi,5,6 Nadir Mustafa Qadir Nanakali,7,8 Asaad AB Alasady,9 Falah Mohammad Aziz,3 Koorosh Shahpasand,10 Anwarul Hasan,11,12 Mojtaba Falahati51Department of Biochemistry and Biophysics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; 2Department of Molecular Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; 3Department of Biology, College of Science, Salahaddin University-Erbil, Kurdistan Region, Iraq; 4Department of Medical Analysis, Faculty of Science, Tishk International University, Erbil, Iraq; 5Department of Nanomedicine, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; 6Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran; 7Department of Biology, College of Science, Cihan University-Erbil, Kurdistan Region, Iraq; 8Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq; 9Anatomy, Biology and Histology Unit, College of Medicine, University of Duhok, Kurdistan Region, Iraq; 10Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; 11Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha 2713, Qatar; 12Biomedical Research Center, Qatar University, Doha 2713, QatarCorrespondence: Mojtaba FalahatiDepartment of Nanomedicine, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, IranEmail mojtaba.falahati@alumni.ut.ac.irAnwarul HasanDepartment of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha 2713, QatarEmail hasan.anwarul.mit@gmail.com*These authors contributed equally to this workAim: Among therapeutic proposals for amyloid-associated disorders, special attention has been given to the exploitation of nanoparticles (NPs) as promising agents against aggregation.Methods: In this paper, the inhibitory effect of cerium oxide (CeO2) NPs against α-synuclein (α-syn) amyloid formation was explored by different methods such as Thioflavin T (ThT) and 8-anilinonaphthalene-1-sulfonic acid (ANS) fluorescence spectroscopy, Congo red adsorption assay, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), and bioinformatical approaches. Also, the cytotoxicity of α-syn amyloid either alone or with CeO2 NPs against neuron-like cells (SH-SY5Y) was examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and quantitative real-time polymerase chain reaction (Bax and Bcl-2 gene expression) assays.Results: ThT and ANS fluorescence assays indicated that CeO2 NPs inhibit the formation of aggregated species and hydrophobic patches of α-syn in amyloidogenic conditions, respectively. Congo red and CD assays demonstrated that CeO2 NPs reduce the formation of amyloid species and β-sheets structures of α-syn molecules, respectively. TEM investigation also confirmed that CeO2 NPs limited the formation of well-defined fibrillary structures of α-syn molecules. Molecular docking and dynamic studies revealed that CeO2 NPs could bind with different affinities to α-syn monomer and amyloid species and fibrillar structure of α-syn is disaggregated in the presence of CeO2 NPs. Moreover, cellular assays depicted that CeO2 NPs mitigate the cell mortality, apoptosis, and the ratio of Bax/Bcl-2 gene expression associated with α-syn amyloids.Conclusion: It may be concluded that CeO2 NPs can be used as therapeutic agents to reduce the aggregation of proteins and mitigate the occurrence of neurodegenerative diseases.Keywords: cerium oxide, nanoparticle, amyloid, cytotoxicity, spectroscopy, cellular assay, inhibition