Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy

• Published in: Nature communications Vol. 15; no. 1; pp. 3684 - 20
• Main Authors: Yan, Jiaqi, Bhadane, Rajendra, Ran, Meixin, Ma, Xiaodong, Li, Yuanqiang, Zheng, Dongdong, Salo-Ahen, Outi M. H., Zhang, Hongbo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 13/89; 49; 631/1647/350/354; 631/45/147; 692/308; Acids; Animals; Aptamers, Nucleotide - chemistry; Aptamers, Nucleotide - metabolism; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; DNA, Catalytic - chemistry; DNA, Catalytic - metabolism; Gastric cancer; Glutathione - chemistry; Glutathione - metabolism; Humanities and Social Sciences; Humans; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Metals; Mice; multidisciplinary; Nanocomposites; Nanotechnology; Nucleic acids; Nucleic Acids - chemistry; Nucleic Acids - metabolism; Reactive Oxygen Species - metabolism; Receptor, ErbB-2 - metabolism; Science; Science (multidisciplinary); Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48149-9

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca 2+ /(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application. The development of metal-nucleic acid nanocomposites for therapeutic is limited by poor stability and synthesis efficiency. Here, the authors develop a multi-fragmented aptamer DNAzyme metal-nucleic acid frameworks (MNFs) under milder conditions and demonstrate its preclinical efficacy in gastric cancer.