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Deciphering chain\u2010length\u2010dependent biosafety and cellular uptake profiles of PEG polymers is vital for optimizing nanomedicine formulations. We established an ultra\u2010high\u2010performance liquid chromatography\u2010tandem mass spectrometry (UHPLC\u2010MS\/MS) methodology employing ammonium adduction for multiplex quantification of PEG600 oligomers (\n                    <jats:italic>n<\/jats:italic>\n                    = 9\u201318) in human hepatocellular carcinoma (HepG2) hepatocytes. The method demonstrated linear response (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    &gt; 0.99) across 10\u20131000\u00a0ng\/mL for PEG600 oligomers (\n                    <jats:italic>n<\/jats:italic>\n                    = 9\u201318). PEG600 oligomers (\n                    <jats:italic>n<\/jats:italic>\n                    = 9\u201318) internalization in HepG2 cells was quantified by the validated UHPLC\u2010MS\/MS method. PEG600 polymers with 9\u201318 subunits could be absorbed into HepG2 cells with a small quantity (less than 0.04%). The cytotoxicity study suggested that the half\u2010maximal inhibitory concentration of PEG600 on HepG2 cells is 31.42\u00a0mg\/mL. PEG600 oligomers demonstrated negligible anti\u2010proliferative effects in HepG2 hepatocytes. This study could provide analytical techniques and critical reference data for cytotoxicity and whole cellular uptake profiles of PEG600 polymers with 9\u201318 subunits in HepG2 cells. This work establishes an analytical framework for assessing the cytotoxicity and cellular uptake kinetics of PEG600 oligomers (\n                    <jats:italic>n<\/jats:italic>\n                    = 9\u201318) in HepG2 cells.\n                  <\/jats:p>","DOI":"10.1002\/jssc.70404","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T12:52:04Z","timestamp":1775479924000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Oligomer\u2010specific Uptake Dynamics of PEG600 With 9\u201318 Subunits in HepG2 Cells by Ultra\u2010High\u2010Performance Liquid Chromatography\u2010Tandem Mass Spectrometry Coupled With Ammonium Adduct Strategy to Enhance Sensitivity"],"prefix":"10.1002","volume":"49","author":[{"given":"Jiye","family":"Tian","sequence":"first","affiliation":[{"name":"Central Hospital of Dalian University of Technology Dalian University of Technology  Dalian P. 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