Ultra-stable Zn/Fe bimetallic DNA nanonetworks enable glucose-deprivation-sensitized ferroptosis for gastric cancer therapy.

Metal-coordinated DNA nanostructures have emerged as promising drug delivery platforms owing to their rapid synthesis and high loading capacity. However, current systems degrade within two weeks, presumably because uniform coordination poorly resists perturbation, and physiological phosphate displaces metal ions from DNA. Here, we overcome this bottleneck by co-coordinating Fe2+ and Zn2+ with DNA to generate heterogeneous networks with locally ordered domains. At an optimized Zn/Fe ratio, the nanoassembly maintains structural integrity for over four months. This month-scale stability moves DNA-metal nanoassemblies beyond freshly prepared formulations, supporting storage, transportation, and on-demand therapeutic applications. Beyond stability, the dual metals deliver orthogonal ferroptosis-directed functions. We engineered a HER-2-targeted nanocomplex (P@H-GDz/Zn/Fe) integrating a Zn2+-activated GLUT1-cleaving DNAzyme and a GPX4-inhibitory peptide. Intracellularly, Fe2+ drives Fenton-like radical generation and mitochondrial stress, while Zn2+ enables DNAzyme-mediated GLUT1 silencing to restrict glucose influx, impair glutathione regeneration, and preferentially sensitize glucose-dependent tumor cells to ferroptosis. GPX4 inhibition further disables lipid peroxide detoxification, collectively amplifying ferroptosis death. The nanocomplex shows markedly greater cytotoxicity toward gastric cancer cells than normal fibroblasts and demonstrates potent efficacy in both subcutaneous and orthotopic models. This work establishes bimetallic coordination as a route to stable DNA-metal nanoassemblies enabling metabolic-sensitized ferroptosis therapy.