Simultaneous disruption of glutathione and 7-dehydrocholesterol antioxidant armor drives lipid peroxidation cascade for robust ferroptotic tumor elimination.

Ferroptosis therapy is fundamentally constrained by the robust and adaptive redox homeostasis networks of tumor cells. Notably, 7-dehydrocholesterol (7-DHC) has recently emerged as a formidable, non-canonical metabolic firewall that directly intercepts lipid peroxyl radicals at the plasma membrane, rendering conventional glutathione (GSH)-depleting strategies insufficient. To overcome the dual-layered antioxidant defense, we developed a TME-responsive nanoreactor (TS/GLA@HMION) to orchestrate a synchronized "fuel-spark-breach" lipid peroxidation (LPO) cascade. The nanoreactor was constructed by co-encapsulating TASIN-1 (TS) and γ-linolenic acid (GLA) within hollow mesoporous iron oxide nanoparticles (HMION). Upon TME-triggered disassembly, the released GLA undergoes targeted metabolic incorporation via ACSL1, massively expanding the membrane-localized substrate pool for peroxidation to serve as the required fuel. The iron oxide framework functions as a continuous catalytic engine, driving a sustained Fenton-like reaction to generate abundant •OH as the essential catalytic spark. Meanwhile, TS-mediated inhibition of 7-DHC biosynthesis eliminates the terminal membrane-associated radical scavenging capacity. Coupling 7-DHC blockade with iron-mediated GSH depletion decisively breaches the cellular antioxidant shields. Consequently, the synergy of substrate enrichment, radical generation, and antioxidant disruption transforms restricted oxidative stress into the strong LPO cascade, presenting a potent metabolic redox paradigm for treating refractory malignancies.