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Recent studies revealed that liquid\u2013liquid phase separation (LLPS) is critical for \u03b1-Syn aggregation. This study investigates the regulatory effects of three food-related natural polyphenols on \u03b1-Syn LLPS and amyloid transition. We discovered that, rather than epigallocatechin gallate (EGCG) and gallic acid (GA), tannic acid (TA) dynamically regulates \u03b1-Syn LLPS by increasing \u03b1-Syn mobility within the condensates. TA promotes \u03b1-Syn condensate fusion but retards the liquid-to-solid phase transition, inhibiting \u03b1-Syn aggregation. Further studies showed that TA strongly blocks \u03b1-Syn seed-induced aggregation in neuronal cells and exerts neuroprotective effects against \u03b1-Syn in Caenorhabditis elegans. Our findings demonstrate that the regulation of LLPS-driven \u03b1-Syn amyloid aggregation by small molecules differs from that of nucleation-dependent deposition, providing new insights into targeting \u03b1-Syn phase separation in the treatment of PD and other protein aggregation-related diseases.<\/jats:p>","DOI":"10.1021\/acs.jafc.5c17436","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:02:15Z","timestamp":1786611735000},"page":"26183-26195","source":"Crossref","is-referenced-by-count":0,"title":["Targeting of \u03b1-Syn\nCondensate Fluidity\nby Natural Polyphenols to Retard the Amyloid Transition and Ameliorate\n\u03b1-Syn-Caused Neurotoxicity"],"prefix":"10.1021","volume":"74","author":[{"given":"Fengshuo","family":"Fan","sequence":"first","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingkuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuelin","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenchao","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1491-6904","authenticated-orcid":true,"given":"Yinghui","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyue","family":"He","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3350-8498","authenticated-orcid":true,"given":"Lingjun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-8034","authenticated-orcid":true,"given":"Haijia","family":"Yu","sequence":"additional","affiliation":[{"name":"Nanjing Normal University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"0","key":"2026090104473025100_cit1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00415-002-1301-4","article-title":"Staging of the intracerebral inclusion\nbody pathology associated with idiopathic Parkinson\u2019s disease\n(preclinical and clinical stages)","volume":"249","author":"Braak","year":"2002","journal-title":"J. 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Neurol."},{"issue":"7362","key":"2026090104473025100_cit7","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/nature10324","article-title":"\u03b1-Synuclein\noccurs physiologically\nas a helically folded tetramer that resists aggregation","volume":"477","author":"Bartels","year":"2011","journal-title":"Nature"},{"key":"2026090104473025100_cit8","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.nbd.2015.12.018","article-title":"Dynamic structural\nflexibility of \u03b1-synuclein","volume":"88","author":"Mor","year":"2016","journal-title":"Neurobiol.\nDis."},{"key":"2026090104473025100_cit9","doi-asserted-by":"publisher","first-page":"669994","DOI":"10.3389\/fmolb.2021.669994","article-title":"Secondary Nucleation\nand the Conservation of Structural Characteristics of Amyloid Fibril\nStrains","volume":"8","author":"Hadi Alijanvand","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"2026090104473025100_cit10","doi-asserted-by":"publisher","first-page":"1250532","DOI":"10.3389\/fnins.2023.1250532","article-title":"Liquid-liquid\nphase separation regulates alpha-synuclein aggregate and mitophagy\nin Parkinson\u2019s disease","volume":"17","author":"Hou","year":"2023","journal-title":"Front. Neurosci."},{"issue":"37","key":"2026090104473025100_cit11","doi-asserted-by":"publisher","first-page":"16792","DOI":"10.1021\/jacs.2c03064","article-title":"Macromolecular Crowding as an Intracellular\nStimulus\nfor Responsive Nanomaterials","volume":"144","author":"Estabrook","year":"2022","journal-title":"J. Am. Chem. 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Rev."},{"issue":"6","key":"2026090104473025100_cit20","doi-asserted-by":"publisher","first-page":"E1009","DOI":"10.1073\/pnas.1610586114","article-title":"A natural\nproduct inhibits the initiation of \u03b1-synuclein aggregation and\nsuppresses its toxicity","volume":"114","author":"Perni","year":"2017","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"issue":"11","key":"2026090104473025100_cit21","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1021\/acschemneuro.1c00098","article-title":"C1 Inhibits Liquid\u2013Liquid\nPhase Separation and Oligomerization of Tau and Protects Neuroblastoma\nCells against Toxic Tau Oligomers","volume":"12","author":"Pradhan","year":"2021","journal-title":"ACS Chem.\nNeurosci."},{"key":"2026090104473025100_cit22","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.saa.2019.02.004","article-title":"A quercetin-based\nflavanoid (rutin) reverses amyloid fibrillation in \u03b2-lactoglobulin\nat pH 2.0 and 358 K","volume":"214","author":"Al-Shabib","year":"2019","journal-title":"Spectrochim. Acta, Part\nA"},{"issue":"3","key":"2026090104473025100_cit23","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202308393","article-title":"Natural Polyphenolic Nanodots for\nAlzheimer\u2019s Disease Treatment","volume":"36","author":"Yang","year":"2024","journal-title":"Adv. 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Neurosci."},{"issue":"10","key":"2026090104473025100_cit26","doi-asserted-by":"publisher","first-page":"2788","DOI":"10.1007\/s11064-016-1995-9","article-title":"Epigallocatechin Gallate (EGCG) Inhibits Alpha-Synuclein Aggregation:\nA Potential Agent for Parkinson\u2019s Disease","volume":"41","author":"Xu","year":"2016","journal-title":"Neurochem. Res."},{"issue":"4","key":"2026090104473025100_cit27","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.3892\/mmr.2018.8470","article-title":"(\u2212)-Epigallocatechin-3-gallate\nmodulates peripheral\nimmunity in the MPTP-induced mouse model of Parkinson\u2019s disease","volume":"17","author":"Zhou","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"2026090104473025100_cit28","doi-asserted-by":"publisher","first-page":"121356","DOI":"10.1016\/j.lfs.2022.121356","article-title":"The effects\nof gallic acid and vagotomy on motor function, intestinal transit,\nbrain electrophysiology and oxidative stress alterations in a rat\nmodel of Parkinson\u2019s disease induced by rotenone","volume":"315","author":"Sheikhpour","year":"2023","journal-title":"Life Sci."},{"issue":"37","key":"2026090104473025100_cit29","doi-asserted-by":"publisher","first-page":"33212","DOI":"10.1021\/acsnano.5c07601","article-title":"Tannic Acid-Iron Complex-Based\nNanozyme Ameliorates Parkinson\u2019s Disease via Relieving Oxidative\nStress and Neuroinflammation","volume":"19","author":"He","year":"2025","journal-title":"ACS Nano"},{"issue":"6","key":"2026090104473025100_cit30","doi-asserted-by":"publisher","first-page":"115761","DOI":"10.1016\/j.celrep.2025.115761","article-title":"\u03b2-synuclein blocks\n\u03b1-synuclein condensate fusion to disrupt the maturation of phase\nseparation","volume":"44","author":"Xu","year":"2025","journal-title":"Cell Rep."},{"issue":"16","key":"2026090104473025100_cit31","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200216","article-title":"Myricetin\nInhibits\n\u03b1-Synuclein Amyloid Aggregation by Delaying the Liquid-to-Solid\nPhase Transition","volume":"23","author":"Xu","year":"2022","journal-title":"ChemBioChem"},{"issue":"34","key":"2026090104473025100_cit32","doi-asserted-by":"publisher","first-page":"30281","DOI":"10.1021\/acsomega.2c03534","article-title":"Curcumin Interacts with \u03b1-Synuclein\nCondensates To Inhibit Amyloid Aggregation under Phase Separation","volume":"7","author":"Xu","year":"2022","journal-title":"ACS Omega"},{"key":"2026090104473025100_cit33","first-page":"1","volume-title":"Maintenance\nof C. elegans","author":"Stiernagle","year":"2006"},{"issue":"4","key":"2026090104473025100_cit34","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.fitote.2011.01.018","article-title":"Antioxidant\nand prooxidant properties of flavonoids","volume":"82","author":"Procha\u0301zkova\u0301","year":"2011","journal-title":"Fitoterapia"},{"issue":"4","key":"2026090104473025100_cit35","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1021\/acs.jafc.6b04538","article-title":"Neuroprotective Effects of Bioavailable Polyphenol-Derived\nMetabolites against Oxidative Stress-Induced Cytotoxicity in Human\nNeuroblastoma SH-SY5Y Cells","volume":"65","author":"Gonza\u0301lez-Sarri\u0301as","year":"2017","journal-title":"J. Agric. Food\nChem."},{"key":"2026090104473025100_cit36","doi-asserted-by":"publisher","DOI":"10.3791\/835-v","article-title":"Application\nof a C. elegans Dopamine\nNeuron Degeneration Assay for the Validation of Potential Parkinson\u2019s\nDisease Genes","volume":"17","author":"Berkowitz","year":"2008","journal-title":"J. Vis. Exp."},{"issue":"2","key":"2026090104473025100_cit37","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1080\/10937404.2021.1884921","article-title":"Xenobiotic metabolism and transport\nin Caenorhabditis elegans","volume":"24","author":"Hartman","year":"2021","journal-title":"J. Toxicol. Environ.\nHealth. B Crit. 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Macromol."},{"issue":"9","key":"2026090104473025100_cit41","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1016\/j.bbapap.2014.04.013","article-title":"Gallic acid interacts\nwith \u03b1-synuclein to prevent the structural collapse necessary\nfor its aggregation","volume":"1844","author":"Liu","year":"2014","journal-title":"Biochim. Biophys. Acta\nGen. Subj."},{"key":"2026090104473025100_cit42","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fbioe.2020.00112","article-title":"Antioxidant Nanoparticles for Concerted\nInhibition of \u03b1-Synuclein Fibrillization, and Attenuation of\nMicroglial Intracellular Aggregation and Activation","volume":"8","author":"Zhao","year":"2020","journal-title":"Front Bioeng Biotechnol"},{"issue":"23","key":"2026090104473025100_cit43","doi-asserted-by":"publisher","first-page":"167855","DOI":"10.1016\/j.jmb.2022.167855","article-title":"EGCG\nhas Dual and Opposing Effects on the N-terminal Region of Self-associating\n\u03b1-synuclein Oligomers","volume":"434","author":"Gr\u00f8nnemose","year":"2022","journal-title":"J. Mol. Biol."},{"issue":"17","key":"2026090104473025100_cit44","doi-asserted-by":"publisher","first-page":"7710","DOI":"10.1073\/pnas.0910723107","article-title":"EGCG remodels mature\nalpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity","volume":"107","author":"Bieschke","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026090104473025100_cit45","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s12035-019-01759-7","article-title":"Gallic Acid Attenuated LPS-Induced\nNeuroinflammation:\nProtein Aggregation and Necroptosis","volume":"57","author":"Liu","year":"2020","journal-title":"Mol. Neurobiol."},{"issue":"1","key":"2026090104473025100_cit46","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1038\/s41467-022-28797-5","article-title":"Spatiotemporal\nmodulations in heterotypic condensates of prion and \u03b1-synuclein\ncontrol phase transitions and amyloid conversion","volume":"13","author":"Agarwal","year":"2022","journal-title":"Nat. Commun."},{"issue":"8","key":"2026090104473025100_cit47","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1038\/s41556-024-01456-1","article-title":"VAMP2 chaperones \u03b1-synuclein in synaptic vesicle\nco-condensates","volume":"26","author":"Wang","year":"2024","journal-title":"Nat. Cell Biol."},{"issue":"8","key":"2026090104473025100_cit48","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1038\/s41556-024-01451-6","article-title":"VAMP2 regulates\nphase\nseparation of \u03b1-synuclein","volume":"26","author":"Agarwal","year":"2024","journal-title":"Nat. Cell Biol."},{"issue":"4","key":"2026090104473025100_cit49","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.3390\/ijms11041321","article-title":"Bioavailability of the polyphenols:\nstatus and controversies","volume":"11","author":"D\u2019Archivio","year":"2010","journal-title":"Int. J. Mol. 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