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PEGylation enhances stability and pharmacokinetics but introduces steric and hydration effects that affect chromatographic behavior without altering the nominal DNA charge. This study investigated the retention and mass\u2010transfer behavior of thymine\u2010based poly(dT) oligomers (9\u201395 bases) modified with poly(ethylene glycol) (PEG) using anion\u2010exchange chromatography with a mechanistic ion\u2010exchange framework. By systematically varying PEG molecular weight and modification site, we examined how PEG\u2010induced changes in molecular size and local interaction environment are reflected in mechanistic retention parameters. PEGylation shifted elution to lower salt concentrations, with more pronounced effects observed for shorter oligomers and mid\u2010position modifications. Model\u2010based analysis revealed that the effective number of binding sites remained unchanged after PEG modification, indicating preserved charge\u2010based binding stoichiometry. In contrast, PEGylation reduced the ion\u2010exchange equilibrium constant, reflecting changes in the local interaction environment. HETP analysis showed that unmodified poly(dT) exhibited a strong retention\u2010dependent decrease in plate height, whereas this dependence was weaker for PEGylated DNA, suggesting that PEGylation modifies intraparticle mass\u2010transfer characteristics through combined steric hindrance and charge\u2010shielding effects. These results provide mechanistic insights into the chromatographic behavior of PEGylated oligonucleotides and a rational basis for optimizing their purification.<\/jats:p>","DOI":"10.1002\/biot.70183","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:51:44Z","timestamp":1769493104000},"source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic Insights Into the Retention and Separation Mechanism of Poly(Ethylene Glycol)\u2010Modified Short Oligonucleotides in Anion\u2010Exchange Chromatography"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-9953","authenticated-orcid":false,"given":"Noriko","family":"Yoshimoto","sequence":"first","affiliation":[{"name":"Department of Applied Chemistry Yamaguchi University  Yamaguchi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoya","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry 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