Near Infrared‐Activatable Platinum‐Decorated Gold Nanostars for Synergistic Photothermal/Ferroptotic Therapy in Combating Cancer Drug Resistance

Ferroptotic cell death results from glutathione peroxidase 4 (GPX4) inactivation and/or glutathione (GSH) depletion. Elevated GSH levels are often found in multidrug‐resistant (MDR) tumor cells, reducing their sensitivity to chemotherapeutic drugs and the efficacy of treatment. MDR cells also acquire a dependency on GPX4, reducing their oxidative stress and promoting their survival. Therefore, the depletion of GSH and inactivation of GPX4 has the potential to be a superior treatment strategy for MDR tumors. Platinum‐decorated gold nanostars (Pt‐AuNS) are presented as a novel metal nanoprodrug for ferroptotic therapy against MDR tumors. Under dark conditions, the synthesized Pt‐AuNS exhibit negligible levels of toxicity. Upon exposure of the Pt‐AuNS to near‐infrared (NIR) light, active metallic (Pt and Au) species are released, subsequently inducing cytotoxicity. The mechanism of action is attributed to GSH depletion and GPX4 inactivation, accumulating lipid hydroperoxides, which in turn leads to ferroptosis. In in vivo xenograft, the MDR cancer model confirmed the NIR light‐activation of Pt‐AuNS prodrugs, resulting in efficient ferroptotic therapeutic action against MDR tumors without long‐term side effects. The findings lay the groundwork for using Pt‐AuNS prodrugs responsive to NIR light as ferroptosis‐inducing agents in chemo‐resistant cancer cells and demonstrate their potential for use in future clinical applications. Platinum‐decorated gold nanostars (Pt‐AuNS) as a novel metal nanoprodrug for combined photothermal‐ferroptotic therapy to combat cancer drug resistance. Upon NIR irradiation, the active metallic (Pt and Au) payloads are released, inducing selective cancer cell death. The mechanism of action is attributed to the intracellular GSH depletion and GPX4 inactivation, leading to a subsequent accumulation of lipid hydroperoxides that executes ferroptosis.