Abstract / Summary
ABSTRACT Tumor‐derived extracellular vesicles (EVs) are emerging as critical mediators of metabolic adaptation, yet their role in orchestrating ferroptosis resistance within the tumor microenvironment remains poorly understood. Here, we show that highly malignant osteosarcoma (OS) cells respond to ferroptotic stress by secreting EVs enriched with Alpha‐enolase (ENO1). These EVs‐ENO1 not only bolster the antioxidant capacity of tumor cells but also confer widespread ferroptosis resistance to macrophages and neutrophils, fostering an immunosuppressive niche. To disrupt this metabolic defense, we developed an OS‐targeting lipid nanoparticle (LNP) system for the synergistic delivery of BAP1 mRNA and ENO1 siRNA. We demonstrate that this dual‐delivery platform enhances ferroptosis through two complementary regulatory pathways, BAP1/SLC7A11 and ENO1/GPX4, leading to potent lipid peroxidation and tumor cell death. In syngeneic orthotopic and lung metastasis models, these targeted LNPs significantly suppress tumor progression and catalyze anti‐tumor immunity by activating M1‐type macrophages and cytotoxic T cells. Our findings identify the secretion of EVs‐ENO1 as a key reactive mechanism against ferroptosis and provide a translatable nanomedicine strategy to overcome metabolic and epigenetic resistance in solid tumors.