Bioactive Iridium Nanoclusters with Glutathione Depletion Ability for Enhanced Sonodynamic‐Triggered Ferroptosis‐Like Cancer Cell Death

Abstract Ferroptosis is a regulated form of necrotic cell death that involves the accumulation of lipid peroxide (LPO) species in an iron‐ and reactive oxygen species (ROS)‐dependent manner. Previous investigations have reported that ferroptosis‐based cancer therapy can overcome the limitations of traditional therapeutics targeting the apoptosis pathway. However, it is still challenging to enhance the antitumor efficacy of ferroptosis due to intrinsic cellular regulation. In this study, a ferroptosis‐inducing agent, i.e., chlorin e6 (Ce6)‐conjugated human serum albumin–iridium oxide (HSA‐Ce6‐IrO 2 , HCIr) nanoclusters, is developed to achieve sonodynamic therapy (SDT)‐triggered ferroptosis‐like cancer cell death. The sonosensitizing role of both Ce6 and IrO 2 within the HCIr nanoclusters exhibits highly efficient 1 O 2 generation capacity upon ultrasound stimulation, which promotes the accumulation of LPO and subsequently induces ferroptosis. Meanwhile, the HCIr can deplete glutathione (GSH) by accelerating Ir (IV)–Ir (III) transition, which further suppresses the activity of glutathione peroxidase 4 (GPX4) to enhance the ferroptosis efficacy. Through in vitro and in vivo experiments, it is demonstrated that HCIr possesses tremendous capacity to reduce the intracellular GSH content, which enhances SDT‐triggered ferroptosis‐like cancer cell death. Thus, an iridium‐nanoclusters‐based ferroptosis‐inducing agent is developed, providing a promising strategy for inducing ferroptosis‐like cancer cell death.