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Visualized and cascade-enhanced gene silencing by smart DNAzyme-graphene nanocomplex

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Abstract

BCL-2 gene as well as its products is recognized as a promising target for the molecular targeted therapy of tumors. However, due to certain defense measures of tumor cells, the therapeutic effect based on the gene silencing of BCL-2 is greatly reduced. Here we fabricate a smart response nucleic acid therapeutic that could silence the gene effectively through a dual-targeted and cascade-enhanced strategy. In brief, nano-graphene oxide (GO), working as a nano-carrier, is loaded with a well-designed DNAzyme, which can target and silence the BCL-2 mRNA. Furthermore, upon binding with the BCL-2 mRNA, the enzymatic activity of the DNAzyme can be initiated, cutting a substrate oligonucleotide to produce an anti-nucleolin aptamer AS1411. Nucleolin, a nucleolar phosphoprotein, is known as a stabilizer of BCL-2 mRNA. Via binding and inactivating the nucleolin, AS1411 can destabilize BCL-2 mRNA. By this means of simultaneously targeting mRNA and its stabilizer in an integrated system, effective silencing of the BCL-2 gene of tumor cells is achieved at both the cellular and in vivo levels. After being dosed with this nucleic acid therapeutic and without any chemotherapeutics, apoptosis of tumor cells at the cellular level and apparent shrinkage of tumors in vivo are observed. By labeling a molecular beacon on the substrate of DNAzyme, visualization of the enzymatic activity as well as the tumor in vivo can be also achieved. Our work presents a pure bio-therapeutic strategy that has positive implications for enhancing tumor treatment and avoiding side effects of chemotherapeutics.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 21575088) and the Natural Science Foundation of Shanghai (No. 19ZR1474200).

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  1. Lingjie Ren and Xiaoxia Chen contributed equally to this work.

Authors and Affiliations

  1. Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Lingjie Ren, Chang Feng, Tianshu Chen, Fan Zhang, Bo Tian & Xiaoli Zhu

  2. School of Medical, Shanghai University, Shanghai, 200444, China

    Chang Feng

  3. Lab for Noncoding RNA and Cancer, School of Life Sciences, Shanghai University, Shanghai, 200444, China

    Lei Ding, Xiaomin Liu, Yanli Li & Zhongliang Ma

  4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China

    Xiaoxia Chen

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  1. Lingjie Ren
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  2. Xiaoxia Chen
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  3. Chang Feng
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Correspondence to Bo Tian or Xiaoli Zhu.

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Ren, L., Chen, X., Feng, C. et al. Visualized and cascade-enhanced gene silencing by smart DNAzyme-graphene nanocomplex. Nano Res. 13, 2165–2174 (2020). https://doi.org/10.1007/s12274-020-2826-5

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