Recent progresses in DNA nanostructure-based biosensors for detection of tumor markers.

DNA has emerged as a promising biomaterial for assembling a variety of nanostructures based on its programmable base pairing. It also has other remarkable properties including stability, prominent biocompatibility, and can easily be modified with functional groups for further applications. In the past few decades, researchers have established various design rules and assembly technologies to improve the stability and complexity of DNA nanostructures. The detection of cancer-associated biomarkers has significant importance in identifying patients with different clinical stages and also in developing adaptive therapeutic strategies. Due to their unique advantages, DNA nanostructures can be designed to serve as universal units to form biosensors for the detection of tumor biomarkers. In this review, we first present a brief introduction of the development of structural DNA nanotechnology. Then we summarize recent strategies for DNA nanostructure-based optical, electrochemical and mass sensitive biosensors in cancer detection. Finally, we discuss the challenges and opportunities these technologies provide.

[1]  C. Fan,et al.  DNA nanostructure-based universal microarray platform for high-efficiency multiplex bioanalysis in biofluids. , 2014, ACS applied materials & interfaces.

[2]  Philip Tinnefeld,et al.  Fluorescence Enhancement at Docking Sites of DNA-Directed Self-Assembled Nanoantennas , 2012, Science.

[3]  D. Xiao,et al.  Target-catalyzed autonomous assembly of dendrimer-like DNA nanostructures for enzyme-free and signal amplified colorimetric nucleic acids detection. , 2016, Biosensors & bioelectronics.

[4]  Fei Zhang,et al.  DNA Origami: Scaffolds for Creating Higher Order Structures. , 2017, Chemical reviews.

[5]  B. Sullenger,et al.  Aptamers as Therapeutics. , 2017, Annual review of pharmacology and toxicology.

[6]  Ruo Yuan,et al.  Ultrasensitive Electrochemiluminescence Biosensor for MicroRNA Detection by 3D DNA Walking Machine Based Target Conversion and Distance-Controllable Signal Quenching and Enhancing. , 2017, Analytical chemistry.

[7]  Juwen Shen,et al.  DNA Tetrahedral Nanostructure-Based Electrochemical miRNA Biosensor for Simultaneous Detection of Multiple miRNAs in Pancreatic Carcinoma. , 2017, ACS applied materials & interfaces.

[8]  Wei Pan,et al.  A DNA Tetrahedron Nanoprobe with Controlled Distance of Dyes for Multiple Detection in Living Cells and in Vivo. , 2017, Analytical chemistry.

[9]  Hongyan Xi,et al.  Y-Shaped DNA Duplex Structure-Triggered Gold Nanoparticle Dimers for Ultrasensitive Colorimetric Detection of Nucleic Acid with the Dark-Field Microscope. , 2017, Analytical chemistry.

[10]  Matthew J. A. Wood,et al.  DNA cage delivery to mammalian cells. , 2011, ACS nano.

[11]  Russell P. Goodman,et al.  Rapid Chiral Assembly of Rigid DNA Building Blocks for Molecular Nanofabrication , 2005, Science.

[12]  K. Y. Loh,et al.  DNAzyme sensors for detection of metal ions in the environment and imaging them in living cells. , 2017, Current opinion in biotechnology.

[13]  Yan Zeng,et al.  Colorimetric detection of DNA by using target catalyzed DNA nanostructure assembly and unmodified gold nanoparticles , 2017, Microchimica Acta.

[14]  Hongyuan Chen,et al.  Self-Assembled DNA Tetrahedral Scaffolds for the Construction of Electrochemiluminescence Biosensor with Programmable DNA Cyclic Amplification. , 2017, ACS applied materials & interfaces.

[15]  Wei Cai,et al.  An electrochemical impedance biosensor for Hg2+ detection based on DNA hydrogel by coupling with DNAzyme-assisted target recycling and hybridization chain reaction. , 2017, Biosensors & bioelectronics.

[16]  Shungui Zhou,et al.  Decomposable quantum-dots/DNA nanosphere for rapid and ultrasensitive detection of extracellular respiring bacteria. , 2018, Biosensors & bioelectronics.

[17]  Wenjuan Ma,et al.  Aptamer-Modified Tetrahedral DNA Nanostructure for Tumor-Targeted Drug Delivery. , 2017, ACS applied materials & interfaces.

[18]  Muling Shi,et al.  Aptasensor with Expanded Nucleotide Using DNA Nanotetrahedra for Electrochemical Detection of Cancerous Exosomes. , 2017, ACS nano.

[19]  Nam-Trung Nguyen,et al.  Electrochemical biosensing strategies for DNA methylation analysis. , 2017, Biosensors & bioelectronics.

[20]  X. Qu,et al.  Metal-Ion-Activated DNAzymes Used for Regulation of Telomerase Activity in Living Cells. , 2017, Chemistry.

[21]  J. Reif,et al.  Construction, analysis, ligation, and self-assembly of DNA triple crossover complexes , 2000 .

[22]  Xianming Li,et al.  A Both-End Blocked Peroxidase-Mimicking DNAzyme for Low-Background Chemiluminescent Sensing of miRNA. , 2017, ACS sensors.

[23]  Ying Lin,et al.  Co‐delivery of microRNA‐21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy , 2017, Cancer science.

[24]  F. Crick,et al.  Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid , 1953, Nature.

[25]  Jie Wu,et al.  Target-induced cyclic DNAzyme formation for colorimetric and chemiluminescence imaging assay of protein biomarkers. , 2017, The Analyst.

[26]  Xiaolei Zuo,et al.  Novel rolling circle amplification and DNA origami-based DNA belt-involved signal amplification assay for highly sensitive detection of prostate-specific antigen (PSA). , 2014, ACS Applied Materials and Interfaces.

[27]  R. Yuan,et al.  Dual-color encoded DNAzyme nanostructures for multiplexed detection of intracellular metal ions in living cells. , 2016, Biosensors & bioelectronics.

[28]  Jie Chao,et al.  DNA Hydrogel with Aptamer-Toehold-Based Recognition, Cloaking, and Decloaking of Circulating Tumor Cells for Live Cell Analysis. , 2017, Nano letters.

[29]  J. Chao,et al.  On-Electrode Synthesis of Shape-Controlled Hierarchical Flower-Like Gold Nanostructures for Efficient Interfacial DNA Assembly and Sensitive Electrochemical Sensing of MicroRNA. , 2016, Small.

[30]  Liuting Mo,et al.  Aptamer-integrated DNA nanostructures for biosensing, bioimaging and cancer therapy. , 2016, Chemical Society reviews.

[31]  S. Yao,et al.  DNA G-Quadruplex-Based Assay of Enzyme Activity. , 2017, Methods in molecular biology.

[32]  Jiye Shi,et al.  Multiple-Armed Tetrahedral DNA Nanostructures for Tumor-Targeting, Dual-Modality in Vivo Imaging. , 2016, ACS applied materials & interfaces.

[33]  N. Seeman,et al.  An immobile nucleic acid junction constructed from oligonucleotides , 1983, Nature.

[34]  Avraham Rasooly,et al.  Self-Assembled DNA Generated Electric Current Biosensor for HER2 Analysis. , 2017, Analytical chemistry.

[35]  H. Ju,et al.  A colorimetric biosensor for detection of attomolar microRNA with a functional nucleic acid-based amplification machine. , 2016, Talanta.

[36]  N. Seeman Nucleic acid junctions and lattices. , 1982, Journal of theoretical biology.

[37]  Weihong Tan,et al.  Fluorescence Resonance Energy Transfer-Based DNA Tetrahedron Nanotweezer for Highly Reliable Detection of Tumor-Related mRNA in Living Cells. , 2017, ACS nano.

[38]  Vasilis Ntziachristos,et al.  DNA‐Nanostructure–Gold‐Nanorod Hybrids for Enhanced In Vivo Optoacoustic Imaging and Photothermal Therapy , 2016, Advanced materials.

[39]  H. Ju,et al.  Bis-three-way junction nanostructure and DNA machineries for ultrasensitive and specific detection of BCR/ABL fusion gene by chemiluminescence imaging , 2016, Scientific Reports.

[40]  B. Åkerman,et al.  Sensing conformational changes in DNA upon ligand binding using QCM-D. Polyamine condensation and Rad51 extension of DNA layers. , 2014, The journal of physical chemistry. B.

[41]  Pekka Orponen,et al.  DNA rendering of polyhedral meshes at the nanoscale , 2015, Nature.

[42]  Jie Chao,et al.  DNA nanotechnology-enabled biosensors. , 2016, Biosensors & bioelectronics.

[43]  N. Seeman,et al.  Tight single-stranded DNA knots. , 1993, Journal of biomolecular structure & dynamics.

[44]  L. Penn,et al.  Quartz crystal microbalance: Sensing cell-substrate adhesion and beyond. , 2018, Biosensors & bioelectronics.

[45]  Philip Tinnefeld,et al.  DNA Origami Nanoantennas with over 5000-fold Fluorescence Enhancement and Single-Molecule Detection at 25 μM. , 2015, Nano letters.

[46]  Hao Yan,et al.  Structural DNA Nanotechnology: State of the Art and Future Perspective , 2014, Journal of the American Chemical Society.

[47]  R. Roskoski Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. , 2017, Pharmacological research.

[48]  Dongfang Wang,et al.  A DNA Walker as a Fluorescence Signal Amplifier. , 2017, Nano letters.

[49]  Chii-Wann Lin,et al.  Aptamer-based colorimetric detection of proteins using a branched DNA cascade amplification strategy and unmodified gold nanoparticles. , 2016, Biosensors & bioelectronics.

[50]  Jing‐Juan Xu,et al.  A novel DNA tetrahedron-hairpin probe for in situ"off-on" fluorescence imaging of intracellular telomerase activity. , 2016, The Analyst.

[51]  Na Li,et al.  DNA Dendrimer-Streptavidin Nanocomplex: an Efficient Signal Amplifier for Construction of Biosensing Platforms. , 2017, Analytical chemistry.

[52]  Yibing Yin,et al.  Catalytic Hairpin Assembly Actuated DNA Nanotweezer for Logic Gate Building and Sensitive Enzyme-Free Biosensing of MicroRNAs. , 2016, Analytical chemistry.

[53]  A. Das,et al.  Recent advances in biosensor development for the detection of cancer biomarkers. , 2017, Biosensors & bioelectronics.

[54]  Shawn M. Douglas,et al.  Folding DNA into Twisted and Curved Nanoscale Shapes , 2009, Science.

[55]  Baoquan Ding,et al.  Self‐Assembled DNA Nanostructures for Biomedical Applications , 2017 .

[56]  Maximilian T. Strauss,et al.  DNA nanotechnology and fluorescence applications. , 2016, Current opinion in biotechnology.

[57]  Haitao Liu,et al.  DNA nanostructure meets nanofabrication. , 2013, Chemical Society reviews.

[58]  P. Rothemund Folding DNA to create nanoscale shapes and patterns , 2006, Nature.

[59]  J. Kjems,et al.  Self-assembly of a nanoscale DNA box with a controllable lid , 2009, Nature.

[60]  V. Adam,et al.  Current trends in electrochemical sensing and biosensing of DNA methylation. , 2017, Biosensors & bioelectronics.

[61]  Hao Yan,et al.  Challenges and opportunities for structural DNA nanotechnology. , 2011, Nature nanotechnology.

[62]  Julianne M. Gibbs-Davis,et al.  Tuning Toehold Length and Temperature to Achieve Rapid, Colorimetric Detection of DNA from the Disassembly of DNA-Gold Nanoparticle Aggregates. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[63]  Kazem Anvari,et al.  The prognostic and therapeutic application of microRNAs in breast cancer: Tissue and circulating microRNAs , 2018, Journal of cellular physiology.

[64]  Francesco Cappello,et al.  Exosome levels in human body fluids: A tumor marker by themselves? , 2017, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[65]  Shusheng Zhang,et al.  Ultrasensitive Detection of DNA and Ramos Cell Using In Situ Selective Crystallization Based Quartz Crystal Microbalance. , 2017, Analytical chemistry.

[66]  Hongyuan Chen,et al.  A surface-confined DNA assembly amplification strategy on DNA nanostructural scaffold for electrochemiluminescence biosensing. , 2018, Biosensors & bioelectronics.

[67]  Jie Chao,et al.  Molecular logic gates on DNA origami nanostructures for microRNA diagnostics. , 2014, Analytical chemistry.

[68]  E. Kool,et al.  The Discovery of Rolling Circle Amplification and Rolling Circle Transcription. , 2016, Accounts of chemical research.

[69]  J. Kjems,et al.  Complexes of DNA with fluorescent dyes are effective reagents for detection of autoimmune antibodies , 2017, Scientific Reports.

[70]  F. Crick Central Dogma of Molecular Biology , 1970, Nature.

[71]  Kemin Wang,et al.  DNA tetrahedron nanostructures for biological applications: biosensors and drug delivery. , 2017, The Analyst.

[72]  Sichun Zhang,et al.  Simultaneous Imaging of Three Tumor-Related mRNAs in Living Cells with a DNA Tetrahedron-Based Multicolor Nanoprobe. , 2017, ACS sensors.

[73]  J. Heberle,et al.  Surface-enhanced infrared absorption spectroscopy (SEIRAS) to probe monolayers of membrane proteins. , 2013, Biochimica et biophysica acta.

[74]  N. Nguyen,et al.  Optical biosensing strategies for DNA methylation analysis. , 2017, Biosensors & bioelectronics.

[75]  N. Seeman,et al.  Design and self-assembly of two-dimensional DNA crystals , 1998, Nature.

[76]  Highly Efficient Electrochemiluminescence Resonance Energy Transfer System in One Nanostructure: Its Application for Ultrasensitive Detection of MicroRNA in Cancer Cells. , 2017, Analytical chemistry.

[77]  Pu Zhang,et al.  Bi-directional DNA Walking Machine and Its Application in an Enzyme-Free Electrochemiluminescence Biosensor for Sensitive Detection of MicroRNAs. , 2017, Analytical chemistry.

[78]  Nannan Liu,et al.  DNA hybridization chain reaction and DNA supersandwich self-assembly for ultrasensitive detection , 2017, Science China Chemistry.

[79]  Vinit Kumar,et al.  DNA Nanotechnology for Cancer Therapy , 2016, Theranostics.

[80]  Howon Lee,et al.  Ultra-sensitive detection of zinc oxide nanowires using a quartz crystal microbalance and phosphoric acid DNA , 2016, Nanotechnology.

[81]  Andreas Walther,et al.  3D DNA Origami Cuboids as Monodisperse Patchy Nanoparticles for Switchable Hierarchical Self-Assembly. , 2016, Nano letters.

[82]  Kemin Wang,et al.  Gold Nanoparticle Loaded Split-DNAzyme Probe for Amplified miRNA Detection in Living Cells. , 2017, Analytical chemistry.

[83]  H. Ju,et al.  Collapse of DNA Tetrahedron Nanostructure for "Off-On" Fluorescence Detection of DNA Methyltransferase Activity. , 2017, ACS applied materials & interfaces.

[84]  N. Seeman,et al.  Antiparallel DNA Double Crossover Molecules As Components for Nanoconstruction , 1996 .

[85]  Na Li,et al.  An in situ assembly of a DNA-streptavidin dendrimer nanostructure: a new amplified quartz crystal microbalance platform for nucleic acid sensing. , 2015, Chemical communications.

[86]  Kai Fan,et al.  Enzyme-free electrochemical detection of microRNA-21 using immobilized hairpin probes and a target-triggered hybridization chain reaction amplification strategy , 2015, Microchimica Acta.

[87]  Xiuhui Li,et al.  Role of exosomal proteins in cancer diagnosis , 2017, Molecular Cancer.

[88]  Mohammad Reza Ganjali,et al.  Recent advances in biosensor technology in assessment of early diabetes biomarkers. , 2018, Biosensors & bioelectronics.

[89]  Jiye Cai,et al.  Silver nanocluster based sensitivity amplification of a quartz crystal microbalance gene sensor , 2016, Microchimica Acta.

[90]  S. Krishnan,et al.  Measuring Ultra-low Levels of Nucleotide Biomarkers Using Quartz Crystal Microbalance and SPR Microarray Imaging Methods: A Comparative Analysis. , 2017, Sensors and actuators. B, Chemical.

[91]  J. Neuzil,et al.  Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy , 2017, Experimental & Molecular Medicine.

[92]  Kemin Wang,et al.  A DNA tetrahedron-based molecular beacon for tumor-related mRNA detection in living cells. , 2016, Chemical Communications.

[93]  Qiao Jiang,et al.  DNA origami as an in vivo drug delivery vehicle for cancer therapy. , 2014, ACS nano.

[94]  Andrew J Turberfield,et al.  The single-step synthesis of a DNA tetrahedron. , 2004, Chemical communications.

[95]  Jiye Shi,et al.  Electrochemical detection of nucleic acids, proteins, small molecules and cells using a DNA-nanostructure-based universal biosensing platform , 2016, Nature Protocols.

[96]  A. El'skaya,et al.  Selective Amplification of SPR Biosensor Signal for Recognition of rpoB Gene Fragments by Use of Gold Nanoparticles Modified by Thiolated DNA , 2017, Nanoscale Research Letters.

[97]  Pranveer Singh SPR Biosensors: Historical Perspectives and Current Challenges , 2016 .

[98]  Wolfgang Fritzsche,et al.  Gold Nanolenses Self-Assembled by DNA Origami , 2017 .

[99]  Yan Deng,et al.  Mass spectrometry-assisted gel-based proteomics in cancer biomarker discovery: approaches and application , 2017, Theranostics.

[100]  Baoquan Ding,et al.  Observation of intracellular interactions between DNA origami and lysosomes by the fluorescence localization method. , 2016, Chemical communications.

[101]  D. Leong,et al.  Clinically Relevant Detection of Streptococcus pneumoniae with DNA-Antibody Nanostructures. , 2017, Analytical chemistry.

[102]  Hao Yan,et al.  Complex wireframe DNA origami nanostructures with multi-arm junction vertices. , 2015, Nature nanotechnology.

[103]  E. Wang,et al.  Recent Advances Based on Nanomaterials as Electrochemiluminescence Probes for the Fabrication of Sensors , 2017 .

[104]  N. Seeman,et al.  Six-helix bundles designed from DNA. , 2005, Nano letters.

[105]  Yan Huang,et al.  Self-Assembled DNA Hydrogel Based on Enzymatically Polymerized DNA for Protein Encapsulation and Enzyme/DNAzyme Hybrid Cascade Reaction. , 2016, ACS applied materials & interfaces.

[106]  Z. Gao,et al.  Amperometric biosensor for microRNA based on the use of tetrahedral DNA nanostructure probes and guanine nanowire amplification , 2017, Microchimica Acta.