A State‐Gated Metallo‐DNAzyme Framework Programs Tumor Stress Vulnerability Through Metabolic Licensing

ABSTRACT Stress‐generating therapeutic materials are commonly optimized to deliver cytotoxic inputs, but delivery alone does not determine whether intracellular stress becomes irreversible damage. Tumor cells can buffer metal‐, redox‐ and mitochondrial stress through glucose‐dependent metabolism, creating a gap between stress exposure and stress execution. Here, we report a tumor‐state‐gated metallo‐DNAzyme framework, C@HGDz 2 1 /CaCu, that introduces metabolic licensing as a programmable material function. The framework couples a miR‐21/APE1‐gated GLUT1 DNAzyme with a Ca/Cu‐partitioned metal–nucleic‐acid architecture and co‐assembled cystine. Tumor‐state logic confines GLUT1 mRNA cleavage to dual‐input cancer‐associated conditions, whereas metal partitioning assigns Ca 2 + to DNAzyme‐compatible catalysis and Cu 2 + to framework persistence and copper‐associated stress within the metabolically rewired cellular state. After HER2‐guided deployment, C@HGDz 2 1 /CaCu suppresses GLUT1 and glycolytic signaling, restores PTEN‐associated signaling and remodels glucose‐derived metabolic buffering. This metabolic remodeling is associated with enhanced engagement of copper‐ and cystine‐dependent oxidative, mitochondrial and cytoskeletal stress. In an orthotopic gastric tumor model, the framework enhances tumor accumulation, shows coordinated metabolic rewiring and stress engagement, and suppresses tumor progression with apparent tolerability under the tested regimen. This work establishes state‐gated metallo‐DNAzyme framework engineering as a strategy for shifting stress‐generating materials from cytotoxic delivery to vulnerability programming.