{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:06:58Z","timestamp":1789564018320,"version":"build-2803163510"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007352","name":"Staatssekretariat f\u00fcr Bildung, Forschung und Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007352","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein stability is crucial in the development of drug formulations and in understanding many aspects of protein behavior. It is known that both thermal and colloidal protein stability are modulated by the presence of small molecules. Because thermal stability is easier to assess than colloidal stability, it is often used as a proxy for evaluating the latter. In this Mini-Review, we argue that these two aspects of stability have to be considered separately, although they should be related in some complex way.<\/jats:p>","DOI":"10.1021\/acs.nanolett.6c03345","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:21:15Z","timestamp":1788438075000},"page":"11965-11970","source":"Crossref","is-referenced-by-count":0,"title":["The Need to\nDistinguish Colloidal and Thermal Stability\nfor Proteins"],"prefix":"10.1021","volume":"26","author":[{"given":"Ce\u0301cilia","family":"Siri","sequence":"first","affiliation":[{"name":"Ecole Polytechnique Fe\u0301de\u0301rale de Lausanne (EPFL) , , ,","place":["Lausanne, Switzerland, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Poliukhina","sequence":"additional","affiliation":[{"name":"Ecole Polytechnique Fe\u0301de\u0301rale de Lausanne (EPFL) , , ,","place":["Lausanne, Switzerland, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2953-3559","authenticated-orcid":true,"given":"Quy Khac","family":"Ong","sequence":"additional","affiliation":[{"name":"Ecole Polytechnique Fe\u0301de\u0301rale de Lausanne (EPFL) , , ,","place":["Lausanne, Switzerland, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4635-6080","authenticated-orcid":true,"given":"Francesco","family":"Stellacci","sequence":"additional","affiliation":[{"name":"Ecole Polytechnique Fe\u0301de\u0301rale de Lausanne (EPFL) , , ,","place":["Lausanne, Switzerland, 1015"]},{"name":"Ecole Polytechnique Fe\u0301de\u0301rale de Lausanne (EPFL) , , ,","place":["Lausanne, Switzerland, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"2","key":"2026091608072463700_cit1","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/S0378-5173(99)00152-0","article-title":"Instability,\nStabilization, and Formulation of Liquid Protein Pharmaceuticals","volume":"185","author":"Wang","year":"1999","journal-title":"Int. J. Pharm."},{"issue":"4","key":"2026091608072463700_cit2","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1007\/s11095-009-0045-6","article-title":"Stability\nof Protein Pharmaceuticals: An Update","volume":"27","author":"Manning","year":"2010","journal-title":"Pharm.\nRes."},{"issue":"9","key":"2026091608072463700_cit3","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1023\/A:1025771421906","article-title":"Physical\nStability of Proteins in Aqueous Solution: Mechanism and Driving Forces\nin Nonnative Protein Aggregation","volume":"20","author":"Chi","year":"2003","journal-title":"Pharm. Res."},{"issue":"13","key":"2026091608072463700_cit4","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.addr.2011.07.006","article-title":"Protein-Excipient\nInteractions: Mechanisms and Biophysical Characterization Applied\nto Protein Formulation Development","volume":"63","author":"Kamerzell","year":"2011","journal-title":"Adv. Drug\nDelivery Rev."},{"issue":"1","key":"2026091608072463700_cit5","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.xphs.2019.10.048","article-title":"Accelerated\nAggregation\nStudies of Monoclonal Antibodies: Considerations for Storage Stability","volume":"109","author":"Wa\u0308lchli","year":"2020","journal-title":"J. Pharm. Sci."},{"issue":"4","key":"2026091608072463700_cit6","first-page":"307","article-title":"The Development\nof Stable Protein\nFormulations: A Close Look at Protein Aggregation, Deamidation, and\nOxidation","volume":"10","author":"Cleland","year":"1993","journal-title":"Crit. Rev. Ther. Drug Carrier Syst."},{"key":"2026091608072463700_cit7","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/978-1-4939-6412-3_9","article-title":"Storage and Lyophilization of Pure Proteins","volume":"1485","author":"O\u0301\u2019Fa\u0301ga\u0301in","year":"2017","journal-title":"Methods Mol. Biol."},{"issue":"8082","key":"2026091608072463700_cit8","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1038\/s41586-025-09506-w","article-title":"Stabilizing Effect of Amino Acids on Protein and Colloidal\nDispersions","volume":"645","author":"Mao","year":"2025","journal-title":"Nature"},{"issue":"4","key":"2026091608072463700_cit9","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1002\/jps.22371","article-title":"Formulation Development\nof Therapeutic Monoclonal Antibodies Using High-Throughput Fluorescence\nand Static Light Scattering Techniques: Role of Conformational and\nColloidal Stability","volume":"100","author":"Goldberg","year":"2011","journal-title":"J. Pharm. Sci."},{"issue":"12","key":"2026091608072463700_cit10","doi-asserted-by":"publisher","first-page":"5126","DOI":"10.1002\/jps.22712","article-title":"High-Throughput\nAssessment of Thermal and Colloidal Stability Parameters for Monoclonal\nAntibody Formulations","volume":"100","author":"He","year":"2011","journal-title":"J. Pharm. Sci."},{"issue":"1","key":"2026091608072463700_cit11","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.abb.2012.09.008","article-title":"Differential\nScanning Calorimetry as a Tool for Protein Folding and Stability","volume":"531","author":"Johnson","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"issue":"1","key":"2026091608072463700_cit12","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein Misfolding,\nFunctional Amyloid, and Human Disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Annu.\nRev. Biochem."},{"issue":"3","key":"2026091608072463700_cit13","doi-asserted-by":"publisher","first-page":"E501","DOI":"10.1208\/aapsj080359","article-title":"Effects\nof Protein Aggregates: An Immunologic Perspective","volume":"8","author":"Rosenberg","year":"2006","journal-title":"AAPS J."},{"issue":"5","key":"2026091608072463700_cit14","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1007\/s11095-012-0965-4","article-title":"Effects of Ionic Strength\nand Sugars\non the Aggregation Propensity of Monoclonal Antibodies: Influence\nof Colloidal and Conformational Stabilities","volume":"30","author":"Saito","year":"2013","journal-title":"Pharm. Res."},{"issue":"2","key":"2026091608072463700_cit15","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/jps.23827","article-title":"Temperature-Ramped Studies on the\nAggregation, Unfolding,\nand Interaction of a Therapeutic Monoclonal Antibody","volume":"103","author":"Menzen","year":"2014","journal-title":"J. Pharm. Sci."},{"issue":"4","key":"2026091608072463700_cit16","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1002\/jps.22384","article-title":"Screening\nof Monoclonal Antibody Formulations Based on High-Throughput Thermostability\nand Viscosity Measurements: Design of Experiment and Statistical Analysis","volume":"100","author":"He","year":"2011","journal-title":"J. Pharm. Sci."},{"issue":"11","key":"2026091608072463700_cit17","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/bip.360261104","article-title":"Protein\nStability Curves","volume":"26","author":"Becktel","year":"1987","journal-title":"Biopolymers"},{"issue":"17","key":"2026091608072463700_cit18","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.2174\/0929867054546564","article-title":"Differential Scanning Calorimetry\nin Life Science: Thermodynamics, Stability, Molecular Recognition\nand Application in Drug Design","volume":"12","author":"Bruylants","year":"2005","journal-title":"Curr. Med. Chem."},{"issue":"1","key":"2026091608072463700_cit19","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s12551-020-00619-2","article-title":"Theory and Applications of Differential\nScanning Fluorimetry in Early-Stage Drug Discovery","volume":"12","author":"Gao","year":"2020","journal-title":"Biophys. Rev."},{"issue":"9","key":"2026091608072463700_cit20","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1038\/nprot.2007.321","article-title":"The Use of\nDifferential Scanning\nFluorimetry to Detect Ligand Interactions That Promote Protein Stability","volume":"2","author":"Niesen","year":"2007","journal-title":"Nat. Protoc."},{"issue":"6","key":"2026091608072463700_cit21","doi-asserted-by":"publisher","first-page":"2876","DOI":"10.1038\/nprot.2006.202","article-title":"Using Circular\nDichroism Spectra to Estimate Protein Secondary Structure","volume":"1","author":"Greenfield","year":"2006","journal-title":"Nat. Protoc."},{"issue":"4","key":"2026091608072463700_cit22","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1107\/S0907444994001216","article-title":"Predicting Protein\nCrystallization from a Dilute Solution\nProperty","volume":"50","author":"George","year":"1994","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"issue":"10","key":"2026091608072463700_cit23","doi-asserted-by":"publisher","first-page":"8487","DOI":"10.1021\/acsnano.5c19213","article-title":"Direct Measurement\nof Protein Pair Interaction Potential","volume":"20","author":"Poliukhina","year":"2026","journal-title":"ACS Nano"},{"issue":"7","key":"2026091608072463700_cit24","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1002\/jps.22506","article-title":"Assessment of Net Charge\nand Protein-Protein Interactions of Different Monoclonal Antibodies","volume":"100","author":"Lehermayr","year":"2011","journal-title":"J. Pharm. Sci."},{"issue":"2","key":"2026091608072463700_cit25","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.ab.2008.03.032","article-title":"Measurement of the\nSecond Osmotic Virial Coefficient for Protein Solutions Exhibiting\nMonomer-Dimer Equilibrium","volume":"377","author":"Alford","year":"2008","journal-title":"Anal. Biochem."},{"issue":"12","key":"2026091608072463700_cit26","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1063\/1.1746740","article-title":"Apparatus\nand Methods for Measurement and Interpretation of the Angular Variation\nof Light Scattering; Preliminary Results on Polystyrene Solutions","volume":"16","author":"Zimm","year":"1948","journal-title":"J. Chem. Phys."},{"issue":"3","key":"2026091608072463700_cit27","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1016\/S0006-3495(02)75513-6","article-title":"Rapid Measurement\nof Protein Osmotic\nSecond Virial Coefficients by Self-Interaction Chromatography","volume":"82","author":"Tessier","year":"2002","journal-title":"Biophys. J."},{"key":"2026091608072463700_cit28","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.ab.2015.08.020","article-title":"The Osmotic\nSecond Virial Coefficient\nfor Protein Self-Interaction: Use and Misuse to Describe Thermodynamic\nNonideality","volume":"490","author":"Wills","year":"2015","journal-title":"Anal. Biochem."},{"issue":"24","key":"2026091608072463700_cit29","doi-asserted-by":"publisher","first-page":"244903","DOI":"10.1063\/5.0088601","article-title":"Universal\nEffective Interactions of Globular Proteins Close to Liquid-Liquid\nPhase Separation: Corresponding-States Behavior Reflected in the Structure\nFactor","volume":"156","author":"Hansen","year":"2022","journal-title":"J. Chem. Phys."},{"issue":"39","key":"2026091608072463700_cit30","doi-asserted-by":"publisher","first-page":"22384","DOI":"10.1039\/D1CP03210K","article-title":"Interactions\nin Protein Solutions Close to Liquid-Liquid Phase Separation: Ethanol\nReduces Attractions via Changes of the Dielectric Solution Properties","volume":"23","author":"Hansen","year":"2021","journal-title":"Phys. Chem. Chem. Phys."},{"issue":"23","key":"2026091608072463700_cit31","doi-asserted-by":"publisher","first-page":"5278","DOI":"10.1021\/bi00138a006","article-title":"Increased Thermal\nStability of Proteins in the Presence of Naturally Occurring Osmolytes","volume":"31","author":"Santoro","year":"1992","journal-title":"Biochemistry"},{"issue":"3","key":"2026091608072463700_cit32","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S0006-3495(85)83932-1","article-title":"The Stabilization\nof Proteins by Osmolytes","volume":"47","author":"Arakawa","year":"1985","journal-title":"Biophys. J."},{"issue":"7","key":"2026091608072463700_cit33","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1002\/jctb.2657","article-title":"Stabilization of\na Monoclonal Antibody during Purification and Formulation by Addition\nof Basic Amino Acid Excipients","volume":"86","author":"Falconer","year":"2011","journal-title":"J. Chem. Technol.\nBiotechnol."},{"issue":"29","key":"2026091608072463700_cit34","doi-asserted-by":"publisher","first-page":"26458","DOI":"10.1074\/jbc.M300815200","article-title":"Why Is Trehalose an Exceptional Protein Stabilizer?: AN ANALYSIS\nOF THE THERMAL STABILITY OF PROTEINS IN THE PRESENCE OF THE COMPATIBLE\nOSMOLYTE TREHALOSE *","volume":"278","author":"Kaushik","year":"2003","journal-title":"J. Biol. Chem."},{"issue":"10","key":"2026091608072463700_cit35","doi-asserted-by":"publisher","first-page":"2725","DOI":"10.1038\/s44318-025-00431-2","article-title":"Molecular Insights\ninto the Effect of 1,6-Hexanediol on FUS Phase Separation","volume":"44","author":"Zheng","year":"2025","journal-title":"EMBO J."},{"issue":"23","key":"2026091608072463700_cit36","doi-asserted-by":"publisher","first-page":"4096","DOI":"10.1016\/j.bpj.2025.09.043","article-title":"The Influence\nof Proline on Surface\nInteractions in Aqueous Solutions","volume":"124","author":"Agg","year":"2025","journal-title":"Biophys.\nJ."},{"issue":"29","key":"2026091608072463700_cit37","doi-asserted-by":"publisher","first-page":"7199","DOI":"10.1021\/acs.jpcb.4c01086","article-title":"Modulating\nWeak Protein-Protein Cross-Interactions\nby the Addition of Free Amino Acids at Millimolar Concentrations","volume":"128","author":"Winkler","year":"2024","journal-title":"J. Phys. Chem. B"},{"issue":"28","key":"2026091608072463700_cit38","doi-asserted-by":"publisher","first-page":"7154","DOI":"10.1021\/acs.jpclett.4c01175","article-title":"Amino Acids\nand Their Biological Derivatives Modulate\nProtein-Protein Interactions in an Additive Way","volume":"15","author":"Xu","year":"2024","journal-title":"J. Phys. Chem. Lett."},{"issue":"50","key":"2026091608072463700_cit39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407633121","article-title":"Amino Acids\nModulate Liquid-Liquid Phase Separation\nin Vitro and in Vivo by Regulating Protein-Protein Interactions","volume":"121","author":"Xu","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"5","key":"2026091608072463700_cit40","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1007\/s00726-021-02980-2","article-title":"Taurine Suppresses\nLiquid-Liquid Phase Separation of Lysozyme Protein","volume":"53","author":"Tsubotani","year":"2021","journal-title":"Amino Acids"},{"key":"2026091608072463700_cit41","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.ejpb.2015.07.025","article-title":"The Second Virial Coefficient as\na Predictor of Protein\nAggregation Propensity: A Self-Interaction Chromatography Study","volume":"96","author":"Quigley","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"issue":"3","key":"2026091608072463700_cit42","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.bpc.2003.09.012","article-title":"Effect of Alcohols\non Aqueous Lysozyme-Lysozyme Interactions from Static Light-Scattering\nMeasurements","volume":"107","author":"Liu","year":"2004","journal-title":"Biophys. Chem."},{"issue":"6","key":"2026091608072463700_cit43","doi-asserted-by":"publisher","first-page":"4211","DOI":"10.1529\/biophysj.105.068551","article-title":"Second Virial Coefficient Studies\nof Cosolvent-Induced\nProtein Self-Interaction","volume":"89","author":"Valente","year":"2005","journal-title":"Biophys. J."},{"issue":"3","key":"2026091608072463700_cit44","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1023\/A:1015825027737","article-title":"Protein-Solvent Interactions in Pharmaceutical\nFormulations","volume":"8","author":"Arakawa","year":"1991","journal-title":"Pharm. Res."},{"issue":"15","key":"2026091608072463700_cit45","doi-asserted-by":"publisher","first-page":"9721","DOI":"10.1073\/pnas.122225399","article-title":"Protein-Solvent\nPreferential Interactions, Protein Hydration, and the Modulation of\nBiochemical Reactions by Solvent Components","volume":"99","author":"Timasheff","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026091608072463700_cit46","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/0076-6879(79)61005-4","article-title":"[3] Measurements\nof Preferential Solvent Interactions by Densimetric Techniques","volume-title":"Enzyme Structure Part H","author":"Lee","year":"1979"},{"key":"2026091608072463700_cit47","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cis.2006.05.018","article-title":"Effect of Salts and Organic Additives on the Solubility\nof Proteins in Aqueous Solutions","volume":"123\u2013126","author":"Ruckenstein","year":"2006","journal-title":"Adv. Colloid\nInterface Sci."},{"key":"2026091608072463700_cit48","doi-asserted-by":"publisher","DOI":"10.5075\/epfl-thesis-10553","volume-title":"Hydrophobic Interaction\nand Its Small Molecule Effect","author":"Mao","year":"2024"},{"issue":"19","key":"2026091608072463700_cit49","doi-asserted-by":"publisher","first-page":"2200600","DOI":"10.1002\/admi.202200600","article-title":"Experimental\nMethod to Distinguish\nbetween a Solution and a Suspension","volume":"9","author":"Xu","year":"2022","journal-title":"Adv. Mater.\nInterfaces"}],"container-title":["Nano Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.nanolett.6c03345","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/nalefd\/article-pdf\/26\/36\/11965\/68140218\/acs.nanolett.6c03345.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/nalefd\/article-pdf\/26\/36\/11965\/68140218\/acs.nanolett.6c03345.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:30:41Z","timestamp":1789561841000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/nalefd\/article\/26\/36\/11965\/5399372\/The-Need-to-Distinguish-Colloidal-and-Thermal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":49,"journal-issue":{"issue":"36","published-online":{"date-parts":[[2026,9,1]]},"published-print":{"date-parts":[[2026,9,16]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.nanolett.6c03345","relation":{},"ISSN":["1530-6984","1530-6992"],"issn-type":[{"value":"1530-6984","type":"print"},{"value":"1530-6992","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}