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Research Article

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

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.

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Graphical Abstract

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

BCL-2 genegene silencingDNAzymegraphene oxideAS1411

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References

[1]
Delbridge, A. R. D.; Strasser, A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015, 22, 1071-1080.
Crossref Google Scholar
[2]
Pettersson, M.; Jernberg-Wiklund, H.; Larsson, L. G.; Sundstrom, C.; Givol, I.; Tsujimoto, Y.; Nilsson, K. Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells. Blood 1992, 79, 495-502.
Crossref Google Scholar
[3]
Ma, L. Y.; Han, M.; Keyoumu, Z.; Wang, H.; Keyoumu, S. Immunotherapy of dual-function vector with both immunostimulatory and B-cell lymphoma 2 (Bcl-2)-silencing effects on gastric carcinoma. Med. Sci. Monit. 2017, 23, 1980-1991.
Crossref Google Scholar
[4]
Du, Y.; Ji, X. K. Bcl-2 down-regulation by small interfering RNA induces Beclin1-dependent autophagy in human SGC-7901 cells. Cell Biol. Int. 2014, 38, 1155-1162.
Crossref Google Scholar
[5]
Konopleva, M.; Letai, A. BCL-2 inhibition in AML: An unexpected bonus? Blood 2018, 132, 1007-1012.
Crossref Google Scholar
[6]
Bhola, P. D.; Letai, A. Mitochondria-judges and executioners of cell death sentences. Mol. Cell 2016, 61, 695-704.
Crossref Google Scholar
[7]
Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer 2005, 5, 876-885.
Crossref Google Scholar
[8]
Yang, W. Q.; Zhang, Y. RNAi-mediated gene silencing in cancer therapy. Expert Opin. Biol. Ther. 2012, 12, 1495-1504.
Crossref Google Scholar
[9]
Chen, X. X.; Chen, T. S.; Ren, L. J.; Chen, G. F.; Gao, X. H.; Li, G. X.; Zhu, X. L. Triplex DNA nanoswitch for pH-sensitive release of multiple cancer drugs. ACS Nano 2019, 13, 7333-7344.
Crossref Google Scholar
[10]
Tai, W. Y.; Li, J. W.; Corey, E.; Gao, X. H. A ribonucleoprotein octamer for targeted siRNA delivery. Nat. Biomed. Eng. 2018, 2, 326-337.
Crossref Google Scholar
[11]
Tai, W. Y.; Gao, X. H. Functional peptides for siRNA delivery. Adv. Drug Deliv. Rev. 2017, 110-111, 157-168.
Crossref Google Scholar
[12]
Karnati, H. K.; Yalagala, R. S.; Undi, R.; Pasupuleti, S. R.; Gutti, R. K. Therapeutic potential of siRNA and DNAzymes in cancer. Tumor Biol. 2014, 35, 9505-9521.
Crossref Google Scholar
[13]
Liao, Z. X.; Chuang, E. Y.; Lin, C. C.; Ho, Y. C.; Lin, K. J.; Cheng, P. Y.; Chen, K. J.; Wei, H. J.; Sung, H. W. An AS1411 aptamer-conjugated liposomal system containing a bubble-generating agent for tumor-specific chemotherapy that overcomes multidrug resistance. J. Control. Release 2015, 208, 42-51.
Crossref Google Scholar
[14]
Zhang, J. J.; Lan, T.; Lu, Y. Molecular engineering of functional nucleic acid nanomaterials toward in vivo applications. Adv. Healthc. Mater. 2019, 8, 1801158.
Crossref Google Scholar
[15]
Chen, X. X.; Zhao, J.; Chen, T. S.; Gao, T.; Zhu, X. L.; Li, G. X. Nondestructive analysis of tumor-associated membrane protein integrating imaging and amplified detection in situ based on dual-labeled DNAzyme. Theranostics 2018, 8, 1075-1083.
Crossref Google Scholar
[16]
Otake, Y.; Soundararajan, S.; Sengupta, T. K.; Kio, E. A.; Smith, J. C.; Pineda-Roman, M.; Stuart, R. K.; Spicer, E. K.; Fernandes, D. J. Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA. Blood 2007, 109, 3069-3075.
Crossref Google Scholar
[17]
Soundararajan, S.; Chen, W.; Spicer, E. K.; Courtenay-Luck, N.; Fernandes, D. J. The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells. Cancer Res. 2008, 68, 2358-2365.
Crossref Google Scholar
[18]
Ishimaru, D.; Zuraw, L.; Ramalingam, S.; Sengupta, T. K.; Bandyopadhyay, S.; Reuben, A.; Fernandes, D. J.; Spicer, E. K. Mechanism of regulation of bcl-2 mRNA by nucleolin and a plus U-rich element-binding factor 1 (AUF1). J. Biol. Chem. 2010, 285, 27182-27191.
Crossref Google Scholar
[19]
He, Z. M.; Zhang, P. H.; Li, X.; Zhang, J. R.; Zhu, J. J. A targeted DNAzyme-nanocomposite probe equipped with built-in Zn2+ arsenal for combined treatment of gene regulation and drug delivery. Sci. Rep. 2016, 6, 22737.
Crossref Google Scholar
[20]
Oun, R.; Moussa, Y. E.; Wheate, N. J. The side effects of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans. 2018, 47, 6645-6653.
Crossref Google Scholar
[21]
Lawrie, T. A.; Gillespie, D.; Dowswell, T.; Evans, J.; Erridge, S.; Vale, L.; Kernohan, A.; Grant, R. Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma. Cochrane Database Syst. Rev. 2019, 8, CD013047.
Crossref Google Scholar
[22]
Cho, E. A.; Moloney, F. J.; Cai, H.; Au-Yeung, A.; China, C.; Scolyer, R. A.; Yosufi, B.; Raftery, M. J.; Deng, J. Z.; Morton, S. W. et al. Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: A phase 1 first-in-human trial (DISCOVER). Lancet 2013, 381, 1835-1843.
Crossref Google Scholar
[23]
Santoro, S. W.; Joyce, G. F. A general purpose RNA-cleaving DNA enzyme. Proc. Natl. Acad. Sci. USA 1997, 94, 4262-4266.
Crossref Google Scholar
[24]
Wang, H. M.; Chen, Y. Q.; Wang, H.; Liu, X. Q.; Zhou, X.; Wang, F. DNAzyme-loaded metal-organic frameworks (MOFs) for self-sufficient gene therapy. Angew. Chem., Int. Ed. 2019, 58, 7380-7384.
Crossref Google Scholar
[25]
Qu, X. M.; Yang, F.; Chen, H.; Li, J.; Zhang, H. B.; Zhang, G. J.; Li, L.; Wang, L. H.; Song, S. P.; Tian, Y. et al. Bubble-mediated ultrasensitive multiplex detection of metal ions in three-dimensional DNA nanostructure-encoded microchannels. ACS Appl. Mater. Interfaces 2017, 9, 16026-16034.
Crossref Google Scholar
[26]
Su, Y. W.; Li, D.; Liu, B. Y.; Xiao, M. S.; Wang, F.; Li, L.; Zhang, X. L.; Pei, H. Rational design of framework nucleic acids for bioanalytical applications. ChemPlusChem 2019, 84, 512-523.
Crossref Google Scholar
[27]
Xiao, M. S.; Lai, W.; Man, T. T.; Chang, B. B.; Li, L.; Chandrasekaran, A. R.; Pei, H. Rationally engineered nucleic acid architectures for biosensing applications. Chem. Rev. 2019, 119, 11631-11717.
Crossref Google Scholar
[28]
Bakshi, S. F.; Guz, N.; Zakharchenko, A.; Deng, H.; Tumanov, A. V.; Woodworth, C. D.; Minko, S.; Kolpashchikov, D. M.; Katz, E. Magnetic field-activated sensing of mRNA in living cells. J. Am. Chem. Soc. 2017, 139, 12117-12120.
Crossref Google Scholar
[29]
Kim, S.; Ryoo, S. R.; Na, H. K.; Kim, Y. K.; Choi, B. S.; Lee, Y.; Kim, D. E.; Min, D. H. Deoxyribozyme-loaded nano-graphene oxide for simultaneous sensing and silencing of the hepatitis C virus gene in liver cells. Chem. Commun. 2013, 49, 8241-8243.
Crossref Google Scholar
[30]
Somasuntharam, I.; Yehl, K.; Carroll, S. L.; Maxwell, J. T.; Martinez, M. D.; Che, P. L.; Brown, M. E.; Salaita, K.; Davis, M. E. Knockdown of TNF-α by DNAzyme gold nanoparticles as an anti-inflammatory therapy for myocardial infarction. Biomaterials 2016, 83, 12-22.
Crossref Google Scholar
[31]
Tian, B.; Wang, C.; Zhang, S.; Feng, L. Z.; Liu, Z. Photothermally enhanced photodynamic therapy delivered by nano-graphene oxide. ACS Nano 2011, 5, 7000-7009.
Crossref Google Scholar
[32]
Feng, L. Z.; Liu, Z. Graphene in biomedicine: Opportunities and challenges. Nanomedicine 2011, 6, 317-324.
Crossref Google Scholar
[33]
Wang, Y.; Li, Z. H.; Hu, D. H.; Lin, C. T.; Li, J. H.; Lin, Y. H. Aptamer/graphene oxide nanocomplex for in situ molecular probing in living cells. J. Am. Chem. Soc. 2010, 132, 9274-9276.
Crossref Google Scholar
[34]
Bennett, C. F. Therapeutic antisense oligonucleotides are coming of age. Annu. Rev. Med. 2019, 70, 307-321.
Crossref Google Scholar
[35]
Dam, D. H. M.; Lee, J. H.; Sisco, P. N.; Co, D. T.; Zhang, M.; Wasielewski, M. R.; Odom, T. W. Direct observation of nanoparticle- cancer cell nucleus interactions. ACS Nano 2012, 6, 3318-3326.
Crossref Google Scholar
[36]
Fan, H. H.; Zhao, Z. L.; Yan, G. B.; Zhang, X. B.; Yang, C.; Meng, H. M.; Chen, Z.; Liu, H.; Tan, W. H. A smart DNAzyme-MnO2 nanosystem for efficient gene silencing. Angew. Chem., Int. Ed. 2015, 54, 4801-4805.
Crossref Google Scholar
[37]
Bagheri, Z.; Ranjbar, B.; Latifi, H.; Zibaii, M. I.; Moghadam, T. T.; Azizi, A. Spectral properties and thermal stability of AS1411 G-quadruplex. Int. J. Biol. Macromol. 2015, 72, 806-811.
Crossref Google Scholar
[38]
Butovskaya, E.; Soldà, P.; Scalabrin, M.; Nadai, M.; Richter, S. N. HIV-1 nucleocapsid protein unfolds stable RNA G-quadruplexes in the viral genome and is inhibited by G-quadruplex ligands. ACS Infect. Dis. 2019, 5, 2127-2135.
Crossref Google Scholar
[39]
Yang, K.; Feng, L. Z.; Liu, Z. Stimuli responsive drug delivery systems based on nano-graphene for cancer therapy. Adv. Drug Deliv. Rev. 2016, 105, 228-241.
Crossref Google Scholar
[40]
Shi, L.; Mu, C. L.; Gao, T.; Chai, W. X.; Sheng, A. Z.; Chen, T. S.; Yang, J.; Zhu, X. L.; Li, G. X. Rhodopsin-like ionic gate fabricated with graphene oxide and isomeric DNA switch for efficient photocontrol of ion transport. J. Am. Chem. Soc. 2019, 141, 8239-8243.
Crossref Google Scholar
[41]
Yang, K.; Feng, L. Z.; Shi, X. Z.; Liu, Z. Nano-graphene in biomedicine: Theranostic applications. Chem. Soc. Rev. 2013, 42, 530-547.
Crossref Google Scholar
[42]
Pan, W. Y.; Huang, C. C.; Lin, T. T.; Hu, H. Y.; Lin, W. C.; Li, M. J.; Sung, H. W. Synergistic antibacterial effects of localized heat and oxidative stress caused by hydroxyl radicals mediated by graphene/iron oxide-based nanocomposites. Nanomedicine 2016, 12, 431-438.
Crossref Google Scholar
[43]
Zhu, X. L.; Shen, Y. L.; Cao, J. P.; Yin, L.; Ban, F. F.; Shu, Y. Q.; Li, G. X. Detection of microRNA SNPs with ultrahigh specificity by using reduced graphene oxide-assisted rolling circle amplification. Chem. Commun. 2015, 51, 10002-10005.
Crossref Google Scholar
[44]
Zhu, X. L.; Sun, L. Y.; Chen, Y. Y.; Ye, Z. H.; Shen, Z. M.; Li, G. X. Combination of cascade chemical reactions with graphene-DNA interaction to develop new strategy for biosensor fabrication. Biosens. Bioelectron. 2013, 47, 32-37.
Crossref Google Scholar
[45]
Liu, Z.; Winters, M.; Holodniy, M.; Dai, H. J. siRNA delivery into human T cells and primary cells with carbon-nanotube transporters. Angew. Chem., Int. Ed. 2007, 46, 2023-2027.
Crossref Google Scholar
[46]
Liu, Z.; Fan, A. C.; Rakhra, K.; Sherlock, S.; Goodwin, A.; Chen, X. Y.; Yang, Q. W.; Felsher, D. W.; Dai, H. J. Supramolecular stacking of doxorubicin on carbon nanotubes for in vivo cancer therapy. Angew. Chem., Int. Ed. 2009, 48, 7668-7672.
Crossref Google Scholar
[47]
Zhu, X. L.; Zhang, H. H.; Feng, C.; Ye, Z. H.; Li, G. X. A dual-colorimetric signal strategy for DNA detection based on graphene and DNAzyme. RSC Adv. 2014, 4, 2421-2426.
Crossref Google Scholar
[48]
Zhu, X. L.; Zhang, B.; Ye, Z. H.; Shi, H.; Shen, Y. L.; Li, G. X. An ATP-responsive smart gate fabricated with a graphene oxide-aptamer-nanochannel architecture. Chem. Commun. 2015, 51, 640-643.
Crossref Google Scholar
[49]
Yang, K.; Zhang, S.; Zhang, G. X.; Sun, X. M.; Lee, S. T.; Liu, Z. Graphene in mice: Ultrahigh in vivo tumor uptake and efficient photothermal therapy. Nano Lett. 2010, 10, 3318-3323.
Crossref Google Scholar
[50]
Yang, K.; Wan, J. M.; Zhang, S.; Tian, B.; Zhang, Y. J.; Liu, Z. The influence of surface chemistry and size of nanoscale graphene oxide on photothermal therapy of cancer using ultra-low laser power. Biomaterials 2012, 33, 2206-2214.
Crossref Google Scholar
[51]
Perrone, R.; Butovskaya, E.; Lago, S.; Garzino-Demo, A.; Pannecouque, C.; Palù, G.; Richter, S. N. The G-quadruplex-forming aptamer AS1411 potently inhibits HIV-1 attachment to the host cell. Int. J. Antimicrob. Agents 2016, 47, 311-316.
Crossref Google Scholar
Nano Research
Volume 13 Issue 8,
August 2020
Pages 2165-2174
DOI: 10.1007/s12274-020-2826-5
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
Topics:
Cell death GenesGrapheneNucleic acidsTumors

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Received: 26 December 2019
Revised: 20 April 2020
Accepted: 21 April 2020
Published: 05 August 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
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