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However, PEG exposure can elicit anti\u2010PEG antibodies (APAs), resulting in accelerated blood clearance and immune responses. To address this, \u201crandomized PEG\u201d (rPEG) is synthesized by incorporating the comonomer glycidyl methyl ether into PEG via anionic ring\u2010opening polymerization. This structural isomer introduces \u201csynthetic point mutations\u201d, impeding APA recognition. The interaction between rPEGs and APAs is systematically investigated in buffer solution using microscale thermophoresis and fluorescence correlation spectroscopy. Increasing comonomer content drastically reduced antibody binding, with rPEGs containing 52 mol% comonomer effectively preventing APA interaction. Monte Carlo simulations confirmed a reduction in consecutive ethylene glycol sequences to less than 16 units crucial for APA recognition. These results establish rPEG as a promising PEG alternative, mitigating immune recognition while retaining key properties. This is of key relevance for next\u2010generation stealth polymers with improved biocompatibility for biomedical applications.<\/jats:p>","DOI":"10.1002\/advs.202521061","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:30:47Z","timestamp":1763544647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Overcoming PEG Antigenicity: Statistical PEG Isomers Reduce Antibody Binding"],"prefix":"10.1002","volume":"13","author":[{"given":"Mareike","family":"Deuker","sequence":"first","affiliation":[{"name":"Max Planck Institute for Polymer Research  Ackermannweg 10 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johannes Gutenberg University Mainz  Duesbergweg 10\u201014 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaloian","family":"Koynov","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Polymer Research  Ackermannweg 10 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9662-8190","authenticated-orcid":false,"given":"Svenja","family":"Morsbach","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Polymer Research  Ackermannweg 10 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9916-3103","authenticated-orcid":false,"given":"Holger","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johannes Gutenberg University Mainz  Duesbergweg 10\u201014 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9591-4638","authenticated-orcid":false,"given":"Katharina","family":"Landfester","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Polymer Research  Ackermannweg 10 55128 Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc00032a002"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00441"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/f19817702053"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2017.09.002"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/MAT.0b013e3181d7b8e3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12762"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600830432"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(03)00108-X"},{"key":"e_1_2_8_9_1","volume-title":"Polymer\u2010Protein Conjugates: From PEGylation and Beyond","author":"Pasut G.","year":"2020"},{"key":"e_1_2_8_10_1","unstructured":"PEG (polyethylene glycol):Medical Device Material Performance Study ECRI Reports U.S. FDA Center for Devices and Radiological Health 2021."},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)40292-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nnano.2016.6"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(05)03575-0"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.09.002"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.6b03109"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3NH00198A"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.07.024"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.6b03437"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/14686996.2019.1627174"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c05922"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joen.2024.09.002"},{"key":"e_1_2_8_22_1","first-page":"10","volume":"371","author":"Vrieze J. d.","year":"2021","journal-title":"Sci. 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