The Atomically Precise Gold/Captopril Nanocluster Au(25)(Capt)(18) Gains Anticancer Activity by Inhibiting Mitochondrial Oxidative Phosphorylation

[Image: see text] Atomically precise gold nanoclusters (AuNCs) are an emerging class of quantum-sized nanomaterials with well-defined molecular structures and unique biophysical properties, rendering them highly attractive for biological applications. We set out to study the impact of different ligand shells of atomically similar nanoclusters on cellular recognition and response. To understand the effects of atomically precise nanoclusters with identical composition on cells, we selected two different water-soluble gold nanoclusters protected with captopril (Capt) and glutathione (GSH): Au(25)(Capt)(18) (CNC) and Au(25)(GSH)(18) (GNC), respectively. We demonstrated that a change of the ligand of the cluster completely changes its biological functions. Whereas both nanoclusters are capable of internalization, only CNC exhibits remarkable cytotoxicity, more specifically on cancer cells. CNC shows enhanced cytotoxicity by inhibiting the OXPHOS of mitochondria, possibly by inhibiting the ATP synthase complex of the electron transport chain (ETC), and by initiating the leakage of electrons into the mitochondrial lumen. The resulting increase in both mitochondrial and total cellular ROS triggers cell death indicated by the appearance of cellular markers of apoptosis. Remarkably, this effect of nanoclusters is independent of any external light source excitation. Our findings point to the prevailing importance of the ligand shell for applications of atomically precise nanoclusters in biology and medicine.