DNA Nanocarriers: Programmed to Deliver.

Simple base-pairing rules of complementarity, perfected by evolution for encoding genetic information, provide unprecedented control over the process of DNA self-assembly. These rules allow us to build exquisite nanostructures and rationally design their morphology, fine-tune their chemical properties, and program their response to environmental stimuli. DNA nanostructures have emerged as promising candidates for transporting drugs across various physiological barriers of the body. In this review, we discuss the strategies used to transform DNA nanostructures into drug delivery vehicles. We provide an overview of recent attempts at using them to deliver small molecule drugs and macromolecular cargoes and present the challenges that lay ahead for these synthetic vectors as they set new paradigms in the field of nanotechnology and medicine.

[1]  H. Pei,et al.  Self-assembled multivalent DNA nanostructures for noninvasive intracellular delivery of immunostimulatory CpG oligonucleotides. , 2011, ACS nano.

[2]  A. Desideri,et al.  Selective targeting and degradation of doxorubicin-loaded folate-functionalized DNA nanocages. , 2018, Nanomedicine : nanotechnology, biology, and medicine.

[3]  Luvena L. Ong,et al.  Three-Dimensional Structures Self-Assembled from DNA Bricks , 2012, Science.

[4]  H. Sleiman,et al.  Development and characterization of gene silencing DNA cages. , 2014, Biomacromolecules.

[5]  Pamela E. Constantinou,et al.  From Molecular to Macroscopic via the Rational Design of a Self-Assembled 3D DNA Crystal , 2009, Nature.

[6]  Baoquan Ding,et al.  Self-Assembled DNA Dendrimer Nanoparticle for Efficient Delivery of Immunostimulatory CpG Motifs. , 2017, ACS applied materials & interfaces.

[7]  Paul W. Wiseman,et al.  Sequence-responsive unzipping DNA cubes with tunable cellular uptake profiles , 2014 .

[8]  Peixuan Guo,et al.  Advancement of the Emerging Field of RNA Nanotechnology , 2017, ACS nano.

[9]  Chengde Mao,et al.  Reversibly switching the surface porosity of a DNA tetrahedron. , 2012, Journal of the American Chemical Society.

[10]  Baoquan Ding,et al.  A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo , 2018, Nature Biotechnology.

[11]  Yacov Hel-Or,et al.  Thought-Controlled Nanoscale Robots in a Living Host , 2016, PloS one.

[12]  Weihong Tan,et al.  DNA nanoflowers for multiplexed cellular imaging and traceable targeted drug delivery. , 2014, Angewandte Chemie.

[13]  Arun Richard Chandrasekaran,et al.  Addressable configurations of DNA nanostructures for rewritable memory , 2017, Nucleic acids research.

[14]  Chunhai Fan,et al.  DNA Nanotechnology-Enabled Drug Delivery Systems. , 2018, Chemical reviews.

[15]  N. Seeman,et al.  Programmable materials and the nature of the DNA bond , 2015, Science.

[16]  T. Gregory,et al.  Coincidence, coevolution, or causation? DNA content, cellsize, and the C‐value enigma , 2001, Biological reviews of the Cambridge Philosophical Society.

[17]  Weihong Tan,et al.  Noncanonical self-assembly of multifunctional DNA nanoflowers for biomedical applications. , 2013, Journal of the American Chemical Society.

[18]  Weihong Tan,et al.  Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics , 2013, Proceedings of the National Academy of Sciences.

[19]  A. Desideri,et al.  Entry, fate and degradation of DNA nanocages in mammalian cells: a matter of receptors. , 2018, Nanoscale.

[20]  S. Kempter,et al.  Enhanced Chemotherapeutic Behavior of Open‐Caged DNA@Doxorubicin Nanostructures for Cancer Cells , 2016, Journal of cellular physiology.

[21]  T. Liedl,et al.  DNA nanotubes as intracellular delivery vehicles in vivo. , 2015, Biomaterials.

[22]  Michael Matthies,et al.  Design and Synthesis of Triangulated DNA Origami Trusses. , 2016, Nano letters.

[23]  Chunhai Fan,et al.  Growth and origami folding of DNA on nanoparticles for high-efficiency molecular transport in cellular imaging and drug delivery. , 2015, Angewandte Chemie.

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

[25]  J. Kjems,et al.  Intracellular Delivery of a Planar DNA Origami Structure by the Transferrin-Receptor Internalization Pathway. , 2016, Small.

[26]  Tianfeng Chen,et al.  A multifunctional DNA origami as carrier of metal complexes to achieve enhanced tumoral delivery and nullified systemic toxicity. , 2016, Biomaterials.

[27]  Hanadi F Sleiman,et al.  Rolling circle amplification-templated DNA nanotubes show increased stability and cell penetration ability. , 2012, Journal of the American Chemical Society.

[28]  A. Monaco,et al.  Oxidised LDL internalisation by the LOX-1 scavenger receptor is dependent on a novel cytoplasmic motif and is regulated by dynamin-2 , 2008, Journal of Cell Science.

[29]  Hao Yan,et al.  Nanocaged enzymes with enhanced catalytic activity and increased stability against protease digestion , 2016, Nature Communications.

[30]  Sandhya P Koushika,et al.  A synthetic icosahedral DNA-based host-cargo complex for functional in vivo imaging. , 2011, Nature communications.

[31]  Dongsheng Liu,et al.  DNA origami/gold nanorod hybrid nanostructures for the circumvention of drug resistance. , 2017, Nanoscale.

[32]  Qiao Jiang,et al.  Visualization of the intracellular location and stability of DNA origami with a label-free fluorescent probe. , 2012, Chemical communications.

[33]  M. I. Setyawati,et al.  DNA Nanostructures Carrying Stoichiometrically Definable Antibodies. , 2016, Small.

[34]  Yonggang Ke,et al.  Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells. , 2018, Journal of the American Chemical Society.

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

[36]  Michael Matthies,et al.  Block Copolymer Micellization as a Protection Strategy for DNA Origami. , 2017, Angewandte Chemie.

[37]  William M. Shih,et al.  Virus-Inspired Membrane Encapsulation of DNA Nanostructures To Achieve In Vivo Stability , 2014, ACS nano.

[38]  C. Mao,et al.  A smart DNA tetrahedron that isothermally assembles or dissociates in response to the solution pH value changes. , 2013, Biomacromolecules.

[39]  Eunjung Kim,et al.  One‐Pot Synthesis of Multiple Protein‐Encapsulated DNA Flowers and Their Application in Intracellular Protein Delivery , 2017, Advanced materials.

[40]  Ping Wang,et al.  Tumor-Penetrating Peptide-Modified DNA Tetrahedron for Targeting Drug Delivery. , 2016, Biochemistry.

[41]  J. Kjems,et al.  DNA nanovehicles and the biological barriers. , 2016, Advanced drug delivery reviews.

[42]  Hélder A Santos,et al.  Cellular delivery of enzyme-loaded DNA origami. , 2016, Chemical communications.

[43]  Tim Liedl,et al.  Cellular immunostimulation by CpG-sequence-coated DNA origami structures. , 2011, ACS nano.

[44]  Georg Krainer,et al.  Structural stability of DNA origami nanostructures in the presence of chaotropic agents. , 2016, Nanoscale.

[45]  T. Dougherty An update on photodynamic therapy applications. , 2002, Journal of clinical laser medicine & surgery.

[46]  P. Yin,et al.  Complex shapes self-assembled from single-stranded DNA tiles , 2012, Nature.

[47]  Elisa Franco,et al.  Programmable RNA microstructures for coordinated delivery of siRNAs. , 2016, Nanoscale.

[48]  A. Desideri,et al.  Receptor-Mediated Entry of Pristine Octahedral DNA Nanocages in Mammalian Cells. , 2016, ACS nano.

[49]  Jonathan Lee Tin Wah,et al.  Observing and Controlling the Folding Pathway of DNA Origami at the Nanoscale. , 2016, ACS nano.

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

[51]  C. Niemeyer,et al.  Designed Intercalators for Modification of DNA Origami Surface Properties. , 2015, Chemistry.

[52]  Hendrik Dietz,et al.  Biotechnological mass production of DNA origami , 2017, Nature.

[53]  Antti-Pekka Eskelinen,et al.  Virus-encapsulated DNA origami nanostructures for cellular delivery. , 2014, Nano letters.

[54]  Arun Richard Chandrasekaran,et al.  Programmable DNA Nanoswitches for Detection of Nucleic Acid Sequences , 2016 .

[55]  Peng Yin,et al.  Genetic encoding of DNA nanostructures and their self-assembly in living bacteria , 2016, Nature Communications.

[56]  Click-based functionalization of a 2'-O-propargyl-modified branched DNA nanostructure. , 2017, Journal of materials chemistry. B.

[57]  B. Nordén,et al.  A new modular approach to nanoassembly: stable and addressable DNA nanoconstructs via orthogonal click chemistries. , 2012, ACS Nano.

[58]  Peixuan Guo,et al.  Thermodynamically Stable RNA three-way junctions as platform for constructing multi-functional nanoparticles for delivery of therapeutics , 2011, Nature Nanotechnology.

[59]  Björn Högberg,et al.  DNA origami delivery system for cancer therapy with tunable release properties. , 2012, ACS nano.

[60]  Qiao Jiang,et al.  A Photosensitizer-Loaded DNA Origami Nanosystem for Photodynamic Therapy. , 2016, ACS nano.

[61]  Peng Yin,et al.  Casting inorganic structures with DNA molds , 2014, Science.

[62]  Paul W K Rothemund,et al.  Sturdier DNA nanotubes via ligation. , 2006, Nano letters.

[63]  Erik Winfree,et al.  Molecular robots guided by prescriptive landscapes , 2010, Nature.

[64]  D. Meldrum,et al.  Stability of DNA origami nanoarrays in cell lysate. , 2011, Nano letters.

[65]  Hélder A. Santos,et al.  Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility , 2017, Advanced healthcare materials.

[66]  Atanu Basu,et al.  Icosahedral DNA nanocapsules by modular assembly. , 2009, Angewandte Chemie.

[67]  Zhen Gu,et al.  Cocoon-Like Self-Degradable DNA Nanoclew for Anticancer Drug Delivery , 2014, Journal of the American Chemical Society.

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

[69]  Philip M. Kelly,et al.  Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. , 2013, Nature nanotechnology.

[70]  A. Chandrasekaran Reconfigurable DNA Nanoswitches for Graphical Readout of Molecular Signals , 2018, Chembiochem : a European journal of chemical biology.

[71]  Arun Richard Chandrasekaran,et al.  Beyond the Fold: Emerging Biological Applications of DNA Origami , 2016, Chembiochem : a European journal of chemical biology.

[72]  Chen-Sheng Yeh,et al.  Near-infrared light-responsive nanomaterials in cancer therapeutics. , 2014, Chemical Society reviews.

[73]  Jung-Won Keum,et al.  Enhanced resistance of DNA nanostructures to enzymatic digestion. , 2009, Chemical communications.

[74]  Shawn M. Douglas,et al.  A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads , 2012, Science.

[75]  M. Ryadnov,et al.  DNA Origami Inside-Out Viruses. , 2018, ACS synthetic biology.

[76]  Veikko Linko,et al.  Cationic polymers for DNA origami coating - examining their binding efficiency and tuning the enzymatic reaction rates. , 2016, Nanoscale.

[77]  T. G. Martin,et al.  Facile and Scalable Preparation of Pure and Dense DNA Origami Solutions , 2014, Angewandte Chemie.

[78]  Faisal A. Aldaye,et al.  Loading and selective release of cargo in DNA nanotubes with longitudinal variation. , 2010, Nature chemistry.

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

[80]  Hendrik Dietz,et al.  Gigadalton-scale shape-programmable DNA assemblies , 2017, Nature.

[81]  Qiao Jiang,et al.  A Self-Assembled DNA Origami-Gold Nanorod Complex for Cancer Theranostics. , 2015, Small.

[82]  Chor Yong Tay,et al.  Cellular processing and destinies of artificial DNA nanostructures. , 2016, Chemical Society reviews.

[83]  Masayuki Endo,et al.  A versatile DNA nanochip for direct analysis of DNA base-excision repair. , 2010, Angewandte Chemie.

[84]  Yonggang Ke,et al.  Two design strategies for enhancement of multilayer-DNA-origami folding: underwinding for specific intercalator rescue and staple-break positioning. , 2012, Chemical science.

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

[86]  Casey Grun,et al.  Programmable self-assembly of three-dimensional nanostructures from 104 unique components , 2017, Nature.

[87]  Tomoki Shiomi,et al.  Design and development of nanosized DNA assemblies in polypod-like structures as efficient vehicles for immunostimulatory CpG motifs to immune cells. , 2012, ACS nano.

[88]  L. Maldonado-Báez,et al.  Clathrin-independent endocytosis: a cargo-centric view. , 2013, Experimental cell research.

[89]  J. Chao,et al.  Rolling circle amplification-based DNA origami nanostructrures for intracellular delivery of immunostimulatory drugs. , 2013, Small.

[90]  W. Tan,et al.  Self-Assembled DNA Immunonanoflowers as Multivalent CpG Nanoagents , 2015, ACS applied materials & interfaces.

[91]  M. Zhang,et al.  A Telomerase-Responsive DNA Icosahedron for Precise Delivery of Platinum Nanodrugs to Cisplatin-Resistant Cancer. , 2018, Angewandte Chemie.

[92]  Cuichen Wu,et al.  Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy. , 2013, Journal of the American Chemical Society.

[93]  Almogit Abu-Horowitz,et al.  Universal computing by DNA origami robots in a living animal , 2014, Nature nanotechnology.

[94]  M. Wong,et al.  Mitochondrial Delivery of Therapeutic Agents by Amphiphilic DNA Nanocarriers. , 2016, Small.

[95]  H. Sleiman,et al.  DNA nanostructure serum stability: greater than the sum of its parts. , 2013, Chemical communications.

[96]  Daniel G. Anderson,et al.  Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery , 2012, Nature nanotechnology.

[97]  M. Çulha,et al.  Lactose-modified DNA tile nanostructures as drug carriers , 2016, Journal of drug targeting.

[98]  Duhee Bang,et al.  Nano-formulation of a photosensitizer using a DNA tetrahedron and its potential for in vivo photodynamic therapy. , 2016, Biomaterials science.

[99]  Kemin Wang,et al.  "Sense-and-Treat" DNA Nanodevice for Synergetic Destruction of Circulating Tumor Cells. , 2016, ACS applied materials & interfaces.

[100]  Chad A Mirkin,et al.  Mechanism for the endocytosis of spherical nucleic acid nanoparticle conjugates , 2013, Proceedings of the National Academy of Sciences.

[101]  Dong-Ming Huang,et al.  Aptamer-conjugated DNA icosahedral nanoparticles as a carrier of doxorubicin for cancer therapy. , 2011, ACS nano.

[102]  Hao Yan,et al.  DNA origami as a carrier for circumvention of drug resistance. , 2012, Journal of the American Chemical Society.

[103]  Yan Liu,et al.  Uncovering the self-assembly of DNA nanostructures by thermodynamics and kinetics. , 2014, Accounts of chemical research.

[104]  P. Dey,et al.  Detection of cellular microRNAs with programmable DNA nanoswitches , 2018, bioRxiv.

[105]  Igor L. Medintz,et al.  Analyzing DNA Nanotechnology: A Call to Arms For The Analytical Chemistry Community. , 2017, Analytical chemistry.

[106]  William M. Shih,et al.  Addressing the Instability of DNA Nanostructures in Tissue Culture , 2014, ACS nano.

[107]  David A Rusling,et al.  Triplex-forming oligonucleotides: a third strand for DNA nanotechnology , 2017, Nucleic acids research.

[108]  V. Birkedal,et al.  Temperature-controlled encapsulation and release of an active enzyme in the cavity of a self-assembled DNA nanocage. , 2013, ACS nano.

[109]  Arun Richard Chandrasekaran,et al.  Evolution of DNA origami scaffolds , 2016 .

[110]  Hao Yan,et al.  A DNA nanostructure platform for directed assembly of synthetic vaccines. , 2012, Nano letters.

[111]  Hanadi F Sleiman,et al.  Development of DNA Nanostructures for High-Affinity Binding to Human Serum Albumin. , 2017, Journal of the American Chemical Society.

[112]  John C C Hsu,et al.  Optimized DNA "Nanosuitcases" for Encapsulation and Conditional Release of siRNA. , 2016, Journal of the American Chemical Society.

[113]  A. Turberfield,et al.  Guiding the folding pathway of DNA origami , 2015, Nature.

[114]  P. Yin,et al.  DNA Nanostructures-Mediated Molecular Imprinting Lithography. , 2017, ACS nano.

[115]  P. L. Xavier,et al.  DNA-based construction at the nanoscale: emerging trends and applications , 2018, Nanotechnology.

[116]  Tim Liedl,et al.  One-Step Formation of "Chain-Armor"-Stabilized DNA Nanostructures. , 2015, Angewandte Chemie.

[117]  Jiye Shi,et al.  Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells. , 2014, Angewandte Chemie.

[118]  Donald E Ingber,et al.  Modulation of the Cellular Uptake of DNA Origami through Control over Mass and Shape. , 2018, Nano letters.

[119]  Ick Chan Kwon,et al.  Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells. , 2013, Chemical communications.

[120]  Xue Han,et al.  Light-Triggered Release of Bioactive Molecules from DNA Nanostructures. , 2016, Nano letters.

[121]  Masayuki Endo,et al.  Photo-cross-linking-assisted thermal stability of DNA origami structures and its application for higher-temperature self-assembly. , 2011, Journal of the American Chemical Society.

[122]  Patrick D. Halley,et al.  Daunorubicin-Loaded DNA Origami Nanostructures Circumvent Drug-Resistance Mechanisms in a Leukemia Model. , 2016, Small.

[123]  T. LaBean,et al.  Toward larger DNA origami. , 2014, Nano letters.