Self-amplifying ROS-responsive trinity nanodelivery system for enhanced cancer therapy.

Ferroptosis has recently emerged as a promising antitumor strategy, yet conventional ferroptosis inducers often suffer from off-target toxicity, poor tumor specificity, and suboptimal regulation of single pathways. Here, we introduce a novel reactive oxygen species (ROS)-responsive trinity nanodelivery system that integrates iron overload, antioxidant inhibition, and substrate supply to achieve cascade amplification of ferroptosis. Ferrocenecarboxaldehyde (Fc-CHO) and RAS-selective lethal 3 (RSL3) are co-assembled at optimal ratios into nanostructures, with arachidonic acid-modified polyethylene glycol (AA-PEG2k) incorporated to enhance stability. Within the tumor microenvironment, Fc-CHO releases Fe2+, triggering a localized ROS burst via the Fenton reaction. The elevated ROS then cleaves AA-PEG2k to release RSL3, which irreversibly inhibits glutathione peroxidase 4 (GPX4) and blocks lipid peroxide detoxification. Concurrently, AA acts as a substrate for lipid peroxidation, amplifying damage to tumor cell membranes. In vitro tumor-on-a-chip experiments as well as in vivo animal study demonstrate strong antitumor efficacy. This work offers a versatile strategy to overcome ferroptosis resistance and lays a solid theoretical foundation for developing precise, ferroptosis-targeted nanomaterials in cancer therapy.