Fabrication of Metal Nuclear Acid Framework to Enable Carrier-Free MNAzyme Self-Delivery for Gastric Cancer Treatment
: Ma, Xiaodong; Yan, Jiaqi; Zhou, Gongting; Li, Yuanqiang; Ran, Meixin; Li, Chengcheng; Chen, Xiaodong; Sun, Weijian; Zhang, Hongbo; Shen, Xian
Publisher: Wiley-VCH
: WEINHEIM
: 2024
: Advanced Functional Materials
: ADVANCED FUNCTIONAL MATERIALS
: ADV FUNCT MATER
: 2406650
: 34
: 45
: 16
: 1616-301X
: 1616-3028
DOI: https://doi.org/10.1002/adfm.202406650
: https://onlinelibrary.wiley.com/doi/full/10.1002/adfm.202406650
: https://research.utu.fi/converis/portal/detail/Publication/457543692
Multi-component deoxyribozymes (MNAzymes) have shown extraordinary potential in precise gene therapy in vitro, however, the in vivo application is limited by complicated delivery systems. Herein, a novel DNA-metal binding mechanism is discovered, and metal-nucleic acid frameworks (MNFs) are built composed of MNAzymes and metal ions, which enable the carrier-free self-delivery of MNAzymes. Metal ions have a high affinity to DNA, however, the binding of metals with DNA at 20-30 base pair long (that normally a MNAzyme has) to form MNF structure is challenged by stringent high-temperature synthesis conditions, poor stability of the products, and lack of targeting capabilities. While, it is discovered that through folding and entanglement of the MNAzyme with an aptamer tail, and prolonging the sequence to 71 base pair, the metal MNAzymes binding is significantly improved and stabilized to MNF structure even at room temperature. Moreover, the aptamer tail also endows MNFs with targeting capabilities. As proof of concept, a carrier-free Ca/MNAzyme delivery system at room temperature, loaded with the model imaging protein BSA-Cy5 is synthesized. This system can effectively target Her-2 positive gastric cancer cells with the Her-2 responsive aptamer tail and initiate dual gene regulation, thereby inducing energy depletion in cancer cells.
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This work was supported by the National Natural Science Foundation of China (Grant No. 82372145 (H.Z.)). It was also supported by the Research Fellow (Grant No. 353146 (H.Z.)), Project (Grant No. 347897 (H.Z.)), Solution for Health Profile (Grant No. 336355 (H.Z.)), and InFLAMES Flagship (Grant No. 337531 (H.Z.)) grants from the Academy of Finland, Finland, The China Food and Health International Pilot Project (H.Z.) funded by the Finnish Ministry of Education and Culture, The Leading Talents in Scientific and Technological Innovation from Zhejiang Provincial Ten Thousand Talents Plan (Grant No. 2019R52021 (X.S.)), The Key Research and Development Program of Zhejiang Province (Grant No. 2021C03120 (X.S.)). The Key Research and Development Program of Wenzhou (Grant No: ZY2021003 (X.S.)), the National Natural Science Foundation (Grant Nos. 82272172 (W.S.), 81972261 (W.S.), the Medical Health Science and Technology key Project of Zhejiang Provincial and Ministry Health Commission (Grant No. WKJ-ZJ-2322 (W.S.)), the Wenzhou Basic Public Welfare Research Project (Grant No. 2021Y0056 (G.Z.)).
