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Liposomal formulations were prepared via thin-film hydration, yielding spherical, well-dispersed vesicles with high encapsulation efficiency (&gt;\u200990%) and a mean hydrodynamic diameter of 177.2\u2009\u00b1\u200930.2\u00a0nm. PEGylation and metformin loading induced significant physicochemical alterations, as confirmed by differential scanning calorimetry and FTIR spectroscopy, reflecting increased bilayer fluidity and headgroup interactions. Cytotoxicity assays revealed a substantial enhancement in antitumor potency: PEGylated liposomal metformin reduced the IC\u2085\u2080 against HepG2 cells to 118.76\u00a0\u03bcg\/mL compared to 2392.81\u00a0\u03bcg\/mL for free metformin\u2014representing a\u2009&gt;\u200920-fold improvement. In Vero cells, IC\u2085\u2080 values were 137.13\u00a0\u03bcg\/mL and 2113.86\u00a0\u03bcg\/mL, respectively, yielding a selectivity index of 1.15. Apoptosis analysis demonstrated increased early and late apoptotic populations, with PEGylated formulations inducing total apoptosis rates of 20.67% in HepG2 cells. Cell cycle profiling revealed marked G\u2080\/G\u2081 arrest, with 78.12% accumulation versus 58.21% in untreated controls. DNA fragmentation analysis via comet assay further supported elevated genotoxic effects in cancer cells. Molecular docking and 100\u00a0ns molecular dynamics simulations confirmed stable binding of metformin to mitochondrial Complex I and CDK4\/cyclin D3, with a total MM-PBSA binding energy of\u2009\u2212\u200927.33\u00a0kcal\/mol in the CDK4 complex. These findings demonstrate that PEGylated liposomal encapsulation substantially enhances the cytotoxic profile of metformin, supporting its advancement as a targeted nanotherapeutic candidate for HCC.<\/jats:p>","DOI":"10.1038\/s41598-025-13280-0","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T09:40:13Z","timestamp":1754559613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["PEGylated liposomal metformin overcomes pharmacokinetic barriers to trigger potent mitochondrial disruption and cell cycle arrest in hepatocellular carcinoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Zeinab A.","family":"Elzanaty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhat W.","family":"Shafaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seifeldin","family":"Elabed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed M.","family":"Omran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"issue":"3","key":"13280_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. 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