Functionalized Gold Nanoclusters Promote Stress Response in COS‐7 Cells

<p dir="ltr">Ultrasmall gold nanoclusters (AuNC) show great promise for application in theranostics due to their unique optical and physicochemical properties; however, the associated nanotoxicology concerns need to be carefully considered because of their high diffusion across the cellular barrier. Herein, new insights into the role of surface modification of 2 nm AuNC on their toxicity with impact on the metabolism of COS-7 fibroblast-like cells are revealed. AuNCs are chemically modified with either a monodentate-thiolated molecule (AuNC-MHA) or a modified-bidentate sulfobetaine zwitterionic molecule (AuNC-ZwBuEt). Uptake and localization inside fibroblasts and the resultant influence on cell ultrastructure are carefully evaluated using scanning transmission electron microscopy (STEM) and cryo-soft-X-ray tomography (cryo-SXT). At concentrations of ≥25 μg Au mL⁻¹, AuNC-ZwBuEt are cytotoxic toward COS-7 cells and are observed to cross the nuclear membrane. Cryo-SXT analysis shows that fibroblasts develop an acute stress response in the form of swollen mitochondria, nuclear membrane blebbing, and large cytoplasmic vacuoles as early as 1 h postexposure. By contrast, AuNC-MHA are not cytotoxic toward COS-7 cells. Endosomal escape and translocation of the AuNC-ZwBuEt into the nucleus and other organelles may be the cause for the observed cytotoxicity and highlight the need for further study of metal nanocluster-cell interactions.</p>