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Here, we investigate polyethylene glycol (PEG) and dextran (DEX) interactions with different model lipid membranes. Using total internal reflection fluorescence microscopy, we observe that PEG and DEX trigger strikingly different membrane responses \u2013 DEX induces extensive membrane remodeling, including localized multilamellar domain formation, while PEG does not. Combining fluorescence spectroscopy, fluorescence anisotropy, and vibrational sum frequency spectroscopy, we show that DEX perturbs lipid headgroup hydration by displacing interfacial water with minimal effects on lipid packing, while PEG largely preserves this hydration layer. We find that membrane binding affinity alone does not determine the extent to which hydrophilic polymers perturb membrane structure and interfacial properties; and that lipid headgroup hydration, rather than lipid charge, is a general regulator of hydrophilic polymer-membrane interactions. This work gives mechanistic insights into how neutral polymers interact with cells and vesicles, with relevance to cell biology and drug delivery.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"739366v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.18.739366","type":"posted-content","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T16:40:13Z","timestamp":1784738413000},"source":"Crossref","is-referenced-by-count":0,"title":["Lipid Headgroup Hydration Regulates Distinct Remodeling of the Membrane Interface by Polyethylene Glycol and Dextran"],"prefix":"10.64898","author":[{"given":"Sayani","family":"Bhunia","sequence":"first","affiliation":[{"name":"Department of Chemistry, Stony Brook University, Stony Brook, NY 11733, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacky","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stony Brook University, Stony Brook, NY 11733, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmytro","family":"Nykypanchuk","sequence":"additional","affiliation":[{"name":"Center for Functional Nanomaterials, Brookhaven National Laboratory, Upton, New York 11973, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simou","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stony Brook University, Stony Brook, NY 11733, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072706210248000_2026.07.18.739366v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cww086"},{"issue":"45","key":"2026072706210248000_2026.07.18.739366v1.2","doi-asserted-by":"crossref","first-page":"35469","DOI":"10.1039\/C4RA13581D","article-title":"Injectable hydrogels based on poly(ethylene glycol) and derivatives as functional biomaterials","volume":"5","year":"2015","journal-title":"RSC Advances"},{"key":"2026072706210248000_2026.07.18.739366v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115973108"},{"key":"2026072706210248000_2026.07.18.739366v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200902672"},{"key":"2026072706210248000_2026.07.18.739366v1.5","doi-asserted-by":"crossref","unstructured":"Sahoo, H. ; Schwille, P . 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