Presentation matters: Identity of gold nanocluster capping agent governs intracellular uptake and cell metabolism

Au nanoclusters (AuNCs) hold tremendous potential to be employed in a wide variety of biological applications. Despite the rapid development in the field of NCs synthesis, a comprehensive understanding of how cells interact with this class of ultra-small nanoparticles (< 2 nm) having defined sizes and surface chemistry, remains poorly understood. In this study, we show that the choice of the surface ligand used to protect AuNCs can significantly perturb cellular uptake and intracellular redox signaling. A panel of monodisperse, atomically precise AuNCs with different core Au atom number (i.e., Au₁₅, Au₁₈ and Au₂₅) protected with either mercaptopropionic acid (MPA) or glutathione (GSH) capping agent were synthesized and their effects on the generation of intracellular reactive oxygen species (ROS), cytotoxicity and genotoxicity of the NCs were assessed. Both mitochondrial superoxide anion (O₂^•–) and cytoplasmic ROS were found to be higher in cells exposed to MPA but not GSH capped AuNCs. The unregulated state of intracellular ROS is correlated to the amount of internalized AuNCs. Interestingly, MPA–AuNCs induction of ROS level did not lead to any detrimental cellular effects such as cell death or DNA damage. Instead, it was observed that the increase in redox status corresponded to higher cellular metabolism and proliferative capacity. Our study illustrates that surface chemistry of AuNCs plays a pivotal role in affecting the biological outcomes and the new insights gained will be useful to form the basis of defining specific design rules to enable rational engineering of ultra-small complex nanostructures for biological applications.