Exposure to high-frequency (HF) electromagnetic fields (EMFs) at 18 GHz was previously found to induce reversible cell permeabilization in eukaryotic cells; however, the fate of internalized foreign objects inside the cell remains unclear. Here, silica core–shell gold nanospheres (Au NS) of 20 ± 5 nm diameter were used to study the localization of Au NS in pheochromocytoma (PC 12) cells after exposure to HF EMFs at 18 GHz. Internalization of Au NS was confirmed using fluorescence microscopy and transmission electron microscopy. Analysis based on corresponding scanning transmission electron microscopy energy-dispersive spectroscopy revealed the presence of the Au NS free within the PC 12 cell membrane, cytoplasm, enclosed within intracellular vesicles and sequestered in vacuoles. The results obtained in this work highlight that exposure to HF EMFs could be used as an efficient technique with potential for effective delivery of drugs, genetic material, and nanomaterials into cells for the purpose of cellular manipulation or therapy.

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.

Nanotoxicity Ultrasmall gold nanoclusters (AuNC) show great promise for application in theranostics due to their unique optical and physicochemical properties. The associated nanotoxicology concerns need to be carefully considered because of their high diffusion across the cellular barrier. In article number http://doi.wiley.com/10.1002/anbr.202200102, Denver P. Linklater, Elena P. Ivanova, and co‐workers reveal 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.