This study presents the development of aptamer-DNAzyme based metal-nucleic acid frameworks (MNFs) for gastric cancer therapy. MNFs, composed of metal ions and DNA sequences, show great potential as functional nanomaterials. However, existing MNFs face challenges such as harsh synthesis conditions, instability, and non-targeting. The researchers found that longer oligonucleotides enhance MNF synthesis efficiency and stability by increasing folding and entanglement probabilities. Longer oligonucleotides also improve metal ion binding, enabling MNFs to load macromolecular drugs at room temperature. Additionally, longer sequences allow for functional expansion, enabling targeted disease therapy. As a proof-of-concept, the researchers developed an IRF-1 loaded Ca²+/aptamer-deoxyribozyme MNF to target regulate GLUT-1 expression in HER-2 positive gastric cancer cells. This MNF disrupts GSH/ROS homeostasis, suppresses DNA repair, and enhances ROS-mediated DNA damage therapy, achieving a 90% tumor inhibition rate. The integration of metals with DNA structures can create powerful materials, with DNAzymes capable of targeting gene regulation through metal ion interaction. MNFs combine the catalytic functions of metal ions with the therapeutic functions of nucleic acid drugs, resembling Metal-Organic Frameworks (MOFs). MNFs offer advantages over MOFs due to the multifunctionality of DNA sequences. The study highlights the importance of DNA sequence length in MNF synthesis, as longer sequences enhance binding capacity with metal ions and improve synthesis efficiency and stability. The researchers designed three DNA fragments of different lengths to investigate MNF synthesis capabilities. The results showed that longer sequences bind more effectively with calcium ions, leading to higher MNF yields. Molecular dynamics simulations confirmed that longer DNA sequences exhibit higher folding and entanglement probabilities, enhancing calcium ion binding. The study also investigated the therapeutic potential of the IRF-1 loaded MNF, demonstrating its ability to target HER-2 positive gastric cancer cells and regulate GLUT-1 expression. The MNF disrupted GSH/ROS homeostasis, suppressed DNA repair, and enhanced ROS-mediated DNA damage therapy. The results showed that the MNF significantly reduced GLUT-1 protein expression, leading to effective cancer cell targeting and treatment. The study also validated the stability and functionality of the MNF in vivo, demonstrating its potential for targeted drug delivery and cancer therapy. The findings highlight the potential of MNFs in improving ROS-mediated DNA damage therapy and expanding their medical applications.This study presents the development of aptamer-DNAzyme based metal-nucleic acid frameworks (MNFs) for gastric cancer therapy. MNFs, composed of metal ions and DNA sequences, show great potential as functional nanomaterials. However, existing MNFs face challenges such as harsh synthesis conditions, instability, and non-targeting. The researchers found that longer oligonucleotides enhance MNF synthesis efficiency and stability by increasing folding and entanglement probabilities. Longer oligonucleotides also improve metal ion binding, enabling MNFs to load macromolecular drugs at room temperature. Additionally, longer sequences allow for functional expansion, enabling targeted disease therapy. As a proof-of-concept, the researchers developed an IRF-1 loaded Ca²+/aptamer-deoxyribozyme MNF to target regulate GLUT-1 expression in HER-2 positive gastric cancer cells. This MNF disrupts GSH/ROS homeostasis, suppresses DNA repair, and enhances ROS-mediated DNA damage therapy, achieving a 90% tumor inhibition rate. The integration of metals with DNA structures can create powerful materials, with DNAzymes capable of targeting gene regulation through metal ion interaction. MNFs combine the catalytic functions of metal ions with the therapeutic functions of nucleic acid drugs, resembling Metal-Organic Frameworks (MOFs). MNFs offer advantages over MOFs due to the multifunctionality of DNA sequences. The study highlights the importance of DNA sequence length in MNF synthesis, as longer sequences enhance binding capacity with metal ions and improve synthesis efficiency and stability. The researchers designed three DNA fragments of different lengths to investigate MNF synthesis capabilities. The results showed that longer sequences bind more effectively with calcium ions, leading to higher MNF yields. Molecular dynamics simulations confirmed that longer DNA sequences exhibit higher folding and entanglement probabilities, enhancing calcium ion binding. The study also investigated the therapeutic potential of the IRF-1 loaded MNF, demonstrating its ability to target HER-2 positive gastric cancer cells and regulate GLUT-1 expression. The MNF disrupted GSH/ROS homeostasis, suppressed DNA repair, and enhanced ROS-mediated DNA damage therapy. The results showed that the MNF significantly reduced GLUT-1 protein expression, leading to effective cancer cell targeting and treatment. The study also validated the stability and functionality of the MNF in vivo, demonstrating its potential for targeted drug delivery and cancer therapy. The findings highlight the potential of MNFs in improving ROS-mediated DNA damage therapy and expanding their medical applications.