A Coordination Nanosystem Enables Endogenous Ferric Ion‐Initiated Multi‐Catalysis for Synergistic Tumor‐Specific Ferroptosis and Gene Therapy

Abstract Emerging evidence demonstrates that inducing ferroptosis, a nonapoptotic programmed cell death mode, holds significant potential for tumor treatment. However, current ferroptosis strategies utilizing exogenous Fenton‐type heavy metal species or introducing glutathione (GSH)/glutathione peroxidase 4 (GPX4) suppressants are hampered by latent adverse effects toward organisms, while utilizing endogenous iron may cause undesirable tumor angiogenesis through specific signaling pathways. Here, a ferric ion (Fe 3+ )‐responsive and DNAzyme‐delivered coordination nanosystem (ZDD) is developed to achieve a novel scheme of synergistic tumor‐specific ferroptosis and gene therapy, which modulates and harnesses the endogenous iron in tumors for inducing ferroptosis while intercepting tumor angiogenesis to enhance therapeutic efficacy. Profiting from the characteristic coordination structure and components, ZDD can not only specifically capture tumor endogenous Fe 3+ into the tumor cells to promote the catalytic generation of hydroxyl radicals (·OH) and superoxide anions (O 2 · − ) under acidic environment and the catalytic GSH oxidation, arousing potent ferroptotic cell death, but also effectively deliver specific DNAzyme and release abundant zinc ion (Zn 2+ ) as a powerful cofactor to activate the biocatalytic cleavage of vascular endothelial growth factor receptor 2 (VEGFR2) gene for angiogenesis suppression. Ultimately, the ZDD‐enabled synergistic therapy prominently inhibited tumor growth and prevented metastasis, representing a promising nanotherapeutic formula for safe and efficient tumor therapy.