Decoy Extracellular Vesicles Overcome Triple‐Negative Breast Cancer Heterogeneity via Membrane‐Cytoplasm‐Mitochondria Cascade Targeting

Abstract Triple‐negative breast cancer (TNBC) exhibits multilevel heterogeneity, including differences in stemness, immune checkpoint (IC) upregulation, and metabolic plasticity, which has resulted in a lack, of comprehensive treatment strategies. Extracellular vesicles (EVs) from exhausted T cells contain high levels of ICs, which allow them to target and block multiple IC ligands in tumor cells, including cancer stem cells (CSCs). TEAD4 is identified as a pivotal gene facilitating CSC growth and immune escape. Consequently, a novel EV delivery system (siT/MOF@EVs), which targets the tumor cell membrane–cytoplasm–mitochondria cascade, is engineered to codeliver TEAD4‐siRNA (siTEAD4) and a mitochondria‐targeting metal–organic framework (T/MOF) to overcome tumor heterogeneity. Extracellularly, EVs act as “decoys” by facilitating the binding of IC ligands to target tumor cells, particularly CSCs, and blocking multiple ICs. Within the cytoplasm, the siTEAD4 adsorbed on the T/MOF surface is released, inhibiting CSCs and overcoming immunotherapy resistance. In mitochondria, cascade catalysis by nanozymes that bind monoatomic Pd and Mn 2+ triggers an oxidative burst. Additionally, siTEAD4 and T/MOF synergistically block aerobic glycolysis and oxidative phosphorylation and induce immunogenic tumor cell death. siT/MOF@EVs overcome TNBC heterogeneity, inhibit tumor growth and metastasis, and induce protective immune memory in an orthotopic TNBC model without systemic toxicity. Significant therapeutic effects are also observed in a patient‐derived organoid xenograft (PDOX) model.