Synergistic Enhancement of Ferroptosis via Mitochondrial Accumulation and Photodynamic-Controlled Release of an Organogold(I) Cluster Prodrug

Effective delivery and controlled release of metallo-prodrugs with sustained activation and rapid response feed the needs of precise medicine in metal chemotherapeutics. However, gold-based anticancer drugs often suffer from detoxification binding and extracellular transfer by sulfur-containing peptides. To address this challenge, we integrate a thiol-activated prodrug strategy of newly prepared hypercoordinated carbon-centered gold(I) clusters (HCGCs) with their photosensitization character to augment the mitochondrial release of Au(I) in tumors. In contrast to the distorted [CAu₄] kernel of a pentanuclear HCGC compound [A5], its dimeric congener [A9] exhibits a symmetrical [{CAu₄}-Au-{CAu₄}] structure with a remarkable hypercarbon-to-Au₄ electron donation. This unique arrangement results in a microsecond long metal-metal-to-ligand charge transfer excited state relative to the nanosecond intraligand excited state of [A5]. Upon light irradiation at 560 nm, [A9] generates active ¹O₂ to oxidize glutathione (GSH) into poorly coordinating GSSG in the cytoplasm and finally promotes subcellular delivery of HCGCs to mitochondria. Moreover, GSH further triggers consecutive release of active [AuPPh₃]⁺ ions to inhibit cytoplasmic glutathione peroxidase GPX4 and mitochondrial thioredoxin reductase TrxR2, which collectively result in accelerated ferroptosis of human bladder cancer EJ cells and show excellent antitumor performance in mouse bladder tumor models.