Parallel Lipid Peroxide Accumulation Strategy Based on Bimetal-Organic Frameworks for Enhanced Ferrotherapy.

Ferroptosis, a nonapoptotic cell-death pathway, is commonly regulated by ether lipid peroxide generation or glutathione consumption. In this work, a parallel lipid peroxide accumulation strategy was designed based on catalytic metal-organic frameworks (MOFs) for enhanced ferrotherapy. The bimetallic MOF was synthesized with iron porphyrin as a linker and cupric ion as a metal node, and erastin, a ferroptosis inducer, was sandwiched between the MOF layers with 4,4'-dipyridyl disulfide as spacers. In a tumor microenvironment, erastin was released from the layered MOFs through glutathione-responsive cleavage. The exfoliated MOFs served as a dual Fenton reaction inducer to generate numerous hydroxyl radicals for the accumulation of lipid peroxide, while erastin-aggravated glutathione depletion down-regulated glutathione peroxidase 4; this then inhibited the consumption of lipid peroxide. Therefore, a parallel lipid peroxide accumulation strategy was established for enhanced ferrotherapy that effectively inhibited tumor growth in live mice, opening up new opportunities to treat apoptosis-insensitive tumors.