A Trojan Horse Nanotrap with a GSH-Responsive Molecular Gate Orchestrates Ferroptosis via Coupled Iron Release and Spatial GPX4 Inhibition

Abstract Disruption of the dynamic equilibrium between ferroptotic execution pathways and cellular defense mechanisms can trigger ferroptosis, providing a compelling strategy for tumor suppression and the circumvention of drug resistance. Here, we engineered a Trojan Horse-inspired nanotrap, MIPGPX4@aMOF@CM, that integrates biomimetic recognition, redox-responsive amorphous MOF (aMOF) chemistry, and molecular imprinting to disrupt metal homeostasis and disable key protective pathways, thereby triggering cascade-amplified ferroptosis. The inner core is a molecularly imprinted polymer (MIP) that selectively recognizes GPX4, while the outer shell consists of a novel iron-based aMOF acting as a redox-activated molecular gate and is further cloaked with a cancer cell membrane. This multifunctional nanoplatform enables tumor-specific iron delivery and spatially controlled GPX4 inhibition. Upon homotypic membrane-mediated tumor targeting and cellular internalization, elevated intracellular glutathione (GSH) triggers aMOF degradation, leading to GSH depletion, iron release, and on-demand exposure of the imprinted GPX4 binding sites. This gate-controlled cascade synergistically promotes Fenton chemistry and GPX4 inactivation, substantially disrupting the balance between ferroptotic execution and antioxidant defenses and enhancing tumor-selective ferroptotic responses. Collectively, this work highlights that precisely orchestrating metal homeostasis, redox regulation, and GPX4 inhibition represents a promising strategy for precision ferroptosis-based cancer therapy.