Supramolecular coordination nanoplatform amplifies oxidative stress to overcome ferroptosis resistance in gallbladder cancer.

Gallbladder cancer (GBC) is a highly aggressive malignancy, and its robust antioxidant defense system frequently leads to profound therapeutic resistance. Targeted disruption of redox homeostasis offers a potential strategy to overcome such resistance. In this study, we developed ICFe@D, a supramolecular nanomedicine co-assembled from iso-liquiritigenin (ISL), Fe³⁺, and chlorin e6 (Ce6) within a DSPE-PEG matrix, to trigger combined ferroptosis and apoptosis. As a tumor microenvironment (TME)-responsive platform, ICFe@D systematically dismantles the antioxidant defenses of GBC cells through a "supply-and-exhaust" mechanism. Specifically, Fe3+-derived Fe2+ and laser-activated Ce6 act as an efficient reactive oxygen species (ROS) generator via Fenton and photodynamic reactions, while ISL severely impairs the intracellular antioxidant capacity by downregulating GPX4 and activating the p62/Keap1/Nrf2/HMOX1 signaling pathway. We evaluated the therapeutic efficacy of this platform in patient-derived organoids (PDOs) and patient-derived organoid xenograft (PDOX) models. ICFe@D demonstrated potent and consistent tumor regression across heterogeneous patient-specific models with minimal systemic toxicity. This study presents a highly translatable and precise nanotherapeutic strategy that effectively sensitizes GBC to ferroptosis, providing a valuable preclinical framework for biliary tract cancer therapy.