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The outcome of their therapeutic delivery applications relies on understanding cell internalization routes. Current literature presents often conflicting results based on surveying only a few endocytosis inhibitors. Herein, a holistic approach to cell uptake studies by utilizing six different inhibitors while considering their on\u2010 and off\u2010target effects on internalization of the GQDs of different charges is provided. Endocytosis paths are explored by tracking intracellular GQD fluorescence in HeLa or HEK\u2010293 cells. Contrary to the previous assumptions of a singular entry route, findings suggest that GQDs enter the cells through several endocytosis paths with some more prevalent than others. Selectivity between the pathways is based on GQD charge and functional groups. Positively charged nitrogen\u2010doped GQDs (NGQDs) predominantly utilize a fast endophilin\u2010mediated endocytosis (FEME) in HeLa cells with a secondary preference for clathrin\u2010mediated endocytosis (CME). In HEK\u2010293 cells NGQDs internalize via clathrin\u2010independent, glycosylphosphatidylinositol\u2010anchored protein\u2010enriched compartments (CLIC\/GEEC) and FEME. Conversely, GQDs with a substantial negative surface charge uptake through CME in HeLa cells. The optimization of these mechanisms can enhance GQD applications in biomedicine, ideally streamlining their translation into the clinic.<\/jats:p>","DOI":"10.1002\/smll.202406095","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T02:36:01Z","timestamp":1738550161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Holistic Investigation of Graphene Quantum Dot Endocytosis"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5345-7782","authenticated-orcid":false,"given":"Ugur C.","family":"Topkiran","sequence":"first","affiliation":[{"name":"Department of Physics and Astronomy Texas Christian University  TCU Box 298840 Fort Worth TX 76129 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3501-4288","authenticated-orcid":false,"given":"Alina 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