This study explores the development of metal-nucleic acid frameworks (MNFs) for gastric cancer therapy, focusing on enhancing their synthesis efficiency, stability, and targeting capabilities. Longer oligonucleotides are found to improve MNF synthesis by increasing folding and entanglement probabilities, facilitating metal ion binding, and enabling the loading of macromolecular drugs. The research specifically targets HER-2 positive gastric cancer cells by incorporating an interferon regulatory factor-1 (IRF-1)-loaded Ca²⁺/(aptamer-deoxyribozyme) MNF to regulate glucose transporter (GLUT-1) expression. This MNF disrupts GSH/ROS homeostasis, suppresses DNA repair, and enhances ROS-mediated DNA damage, achieving a tumor inhibition rate of up to 90%. The study highlights the potential of MNFs in cancer treatment, particularly in ROS-mediated DNA damage therapy, and expands their medical application scope.This study explores the development of metal-nucleic acid frameworks (MNFs) for gastric cancer therapy, focusing on enhancing their synthesis efficiency, stability, and targeting capabilities. Longer oligonucleotides are found to improve MNF synthesis by increasing folding and entanglement probabilities, facilitating metal ion binding, and enabling the loading of macromolecular drugs. The research specifically targets HER-2 positive gastric cancer cells by incorporating an interferon regulatory factor-1 (IRF-1)-loaded Ca²⁺/(aptamer-deoxyribozyme) MNF to regulate glucose transporter (GLUT-1) expression. This MNF disrupts GSH/ROS homeostasis, suppresses DNA repair, and enhances ROS-mediated DNA damage, achieving a tumor inhibition rate of up to 90%. The study highlights the potential of MNFs in cancer treatment, particularly in ROS-mediated DNA damage therapy, and expands their medical application scope.