Construction of Active Sites‐Accessible Au₈ Clusters for Intensive Tumor Pyroptosis

ABSTRACT Atomically precise gold nanoclusters (NCs), possessing characteristics of molecules and nanoparticles, offer a promising solution to the challenges faced by existing pyroptosis inducers. Their abilities to catalyze the generation of reactive oxygen species and enhance radiosensitization position them as effective agents for activating pyroptosis. However, their catalytic efficiency is often compromised by limited geometrically accessible spaces around the active sites and the lack of suitable ligands. Leveraging the exposed metal centers in mononuclear organometallic catalysts and the tunable ligand of NCs, herein, ethynylferrocene (EFc) was utilized to amplify the peroxidase (POD)‐like activity of gold NCs by establishing the unshielded catalytic center and electron donor‐acceptor interaction between EFc and Au core. The resulting Au 8 Fe 2 NCs with excellent POD‐mimicking activity could efficiently trigger pyroptosis by inducing intracellular oxidative stress. Moreover, the Au 8 Fe 2 NCs, with their potential to deplete glutathione and enable magnetic resonance imaging, could also induce ferroptosis and serve as a diagnostic tool for tumors. All of these processes can be further potentiated by X‐ray radiation, taking advantage of the high atomic number of gold. This work opens new avenues for engineering the catalytic properties of NCs and broadens their potential applications in biomedicine.