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Nano Research 2020, 13(8): 2165-2174 https://doi.org/10.1007/s12274-020-2826-5
Research Article | Issue | Published: 05 August 2020

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

Show Author's Information Lingjie Ren1,§,  Xiaoxia Chen4,§,  Chang Feng1,2,  Lei Ding3,  Xiaomin Liu3,  Tianshu Chen1,  Fan Zhang1,  Yanli Li3,  Zhongliang Ma3,  Bo Tian1( ),  Xiaoli Zhu1( )
Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, China
School of Medical, Shanghai University, Shanghai 200444, China
Lab for Noncoding RNA and Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China

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

Keywords:
graphene oxide, gene silencing, AS1411, BCL-2 gene, DNAzyme
Topics:
Cell death GenesGrapheneNucleic acidsTumors
Cite this article:
Ren L, Chen X, Feng C, et al. Visualized and cascade-enhanced gene silencing by smart DNAzyme-graphene nanocomplex. Nano Research, 2020, 13(8): 2165-2174. https://doi.org/10.1007/s12274-020-2826-5
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Abstract Full text Electronic supplementary material About this article

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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Electronic supplementary material
About this article

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

Show Author's information Lingjie Ren1,§, Xiaoxia Chen4,§, Chang Feng1,2, Lei Ding3, Xiaomin Liu3, Tianshu Chen1, Fan Zhang1, Yanli Li3, Zhongliang Ma3, Bo Tian1( ), Xiaoli Zhu1( )
Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, China
School of Medical, Shanghai University, Shanghai 200444, China
Lab for Noncoding RNA and Cancer, School of Life Sciences, Shanghai University, Shanghai 200444, China
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China

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

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.

Keywords: graphene oxide, gene silencing, AS1411, BCL-2 gene, DNAzyme

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Publication history
Copyright
Acknowledgements

Publication history

Received: 26 December 2019
Revised: 20 April 2020
Accepted: 21 April 2020
Published: 05 August 2020
Issue date: August 2020

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

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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