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In this study, ultrasmall GNPs were synthesized via a solvent-polarity-controlled microwave-assisted reduction method using sodium citrate as a reducing agent and polyvinylpyrrolidone as a stabilizer. The synthesized GNPs exhibited a mean diameter of 6\u2009\u00b1\u20092\u00a0nm and were subsequently employed to investigate the formation and biological implications of a \u03b3-globulin protein corona. Physicochemical characterization demonstrated that \u03b3-globulin adsorption significantly altered the colloidal properties of GNPs, resulting in increased hydrodynamic size, reduced zeta potential, and a red-shift of the surface plasmon resonance band. Fluorescence quenching studies revealed a spontaneous interaction between GNPs and \u03b3-globulin. Thermodynamic analysis indicated that the binding process was predominantly driven by hydrogen bonding and van der Waals interactions. Molecular docking using Au\u2081\u2083 and Au\u2084\u2083 clusters as computationally tractable models of the GNP surface further confirmed the involvement of polar amino acid residues in protein adsorption. Spectroscopic analyses showed only minor conformational perturbations in \u03b3-globulin following interaction with GNPs. Biological evaluation demonstrated that bare GNPs exerted significant selective antiproliferative activity against HepG2 hepatocellular carcinoma cells relative to normal human hepatic L-02 cells, whereas \u03b3-globulin-coated GNPs exhibited markedly reduced cytotoxicity. Protein corona formation decreased cellular uptake, attenuated reactive oxygen species generation, preserved antioxidant defenses, and reduced apoptosis-related signaling. These findings establish a direct mechanistic relationship between \u03b3-globulin corona formation, nanoparticle physicochemical properties, cellular uptake, and biological response, highlighting the critical role of the nano\u2013bio interface in determining the therapeutic performance of GNP-based systems.<\/jats:p>","DOI":"10.1186\/s13065-026-01868-0","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:50:11Z","timestamp":1783007411000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microwave synthesis of ultrasmall gold nanoparticles, their \u03b3-globulin interaction and subsequent effects in hepatocellular carcinoma cells"],"prefix":"10.1186","volume":"20","author":[{"given":"Gong","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"1868_CR1","doi-asserted-by":"crossref","unstructured":"Falahati M, et al. 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