Since Seeman’s pioneering work in the early 1980s , DNA nanotechnology has attracted increasing attention because of the unparalleled ability of DNA molecules in self-assembly. Owing to the excellent physicochemical stability and the high specificity of Watson-Crick basepairing, DNA has emerged as a powerful nanoscale building block for the construction of nanostructures with well-defined geometry. DNA is comprised of four canonical bases with A-T and G-C pairings, hence providing a precise means of programing DNA hybridization processes via rational design of the sequence. Over the past several decades, by exploiting the unique self-recognition properties of DNA molecules, researchers have created a collection of ‘art-like’ DNA nanostructures [1-6], molecular computers [7-9] and nanomachines [10-14].
The versatile chemistry of DNA allows for easy functionalization with a variety of molecules and nanoparticles , therefore offering a promising approach for building artificial functional systems using DNA nanostructured scaffold in combination with various decorations. For instance, Yan et al. designed and constructed a tweezer-like DNA nanodevice with the ability to actuate the inhibition and activation of a G6pDH/NAD+ enzyme/cofactor pair in response to external stimuli. In addition, many of the DNA or DNA nano-structures have been utilized as linkers or templates to mediate the assembly of metal nanoparticles (NPs) into complex plasmonic architectures [17-19]. As a proof of concept, Ding group designed a 2D rectangular DNA origami sheet, in which AuNPs could be assembled due to its well-controlled positions and particle spacing , and 3D plasmonic chiral nanostructures were achieved by rolling the 2D origami template. In addition to its important role as building blocks in nanodevices, DNA also serves as an excellent molecular recognition element in biosensors. A critical challenge in DNA nanostructurebased biosensors lies in controlling the structure of the self-assembled DNA film at the biosensing interface, which plays an important role in the performance of
biosensors. It is thus of paramount importance to obtain an in-depth understanding of the physical structure of immobilized DNA layers. Given the biological nature of DNA nanostructures, they have shown good cellular biocompatibility with minimal cytotoxicity. Therefore, DNA nanostructures have attracted much interest in theranostic applications . In this review, we summarize recent progress in the development of DNA nanostructures in one, two and three dimensions, with a highlight on their biological applications, particularly diagnostics and therapeutics. We apologize for not being able to include all important works in this field due to limitation of space.
2 Assembly of DNA nanostructures
Researchers have constructed a variety of DNA objects (an example shown in Figure 1A). Some examples include cubes [Chen, 1991 #61][22, 23], tetrahedra [24, 25], octahedra [26, 27], icosahedra [28, 30], dodecahedra , prisms  and buckyballs [He, 2008 #65]. DNA-based objects can also be tailored to contain a release mechanism, thereby making them useful for drug delivery and theranostics [31-34].
A variety of rigid DNA motifs have been designed for robust self-assembly of nanostructures based on DNA. For example, the double crossover (DX) motif was used to demonstrate the assembly of the first two dimensional crystalline DNA arrays (Figure 1B) . Other motifs used in the creation of 2D lattices are the triple-crossover (TX) motif , a cross-shaped double-decker tile , a tensegrity triangle with duplex  and double crossover edges , a three-point-star motif where each arm is a four-way junction , a four-point-star (cross) motif  and a sixpoint-star motif . Recently, a motif based on paranemic crossover (PX) DNA was used to create 2D arrays [42, 43]. Such 2D arrays are useful as programmable scaffolds for the organization of nanoparticles and biomolecules .
Seeman and colleagues constructed the first designed three dimensional array using the tensegrity triangle motif (Figure 1C) . The tensegrity triangle is a rigid DNA motif formed from three double helices connected at the vertices by four arm junctions . The triangle motif contains seven DNA strands (or three unique strands in a threefold symmetric version). The ends of the duplex edges contain unpaired nucleotides that are complementary to those on the other end of the edge, thereby allowing one triangle to connect to six such triangles via sticky ends. This assembly continues infinitely in three directions leading to the formation of an infinite periodic lattice (i.e. a crystal) . The edges of the tensegrity triangle motif can be designed to contain desired number of helical turns thus leading to crystals with varying cavity sizes. For example, crystals have been designed and assembled using tensegrity triangle motifs containing 2, 3 or 4 double helical turns of DNA [45, 46]. These designed DNA crystals have been used to host a triplex-forming oligonucleotide , a polyaniline molecule , a color changing strand displacement-based device  and as a system to study torsionally stressed DNA . The goal of such designed DNA crystals is to host external molecules (specifically macromolecules such as hard-to-crystallize proteins) and aid in structure determination of the guests.
A more frequently used method to create DNA nanostructures is DNA origami, where a long single stranded scaffold DNA (usually the viral genome M13) is folded by hundreds of short complementary staple strands into any desired shape (Figure 1D) . The highlight of the DNA origami method is that it does not require purification or a stoichiometric mixture of component strands like tile-based assembly. This strategy has been used in the construction of twisted bundles , three-dimensional multilayer structures  and hollow 3D structures such as boxes , spheres and flasks . Recently, the folding pathways of the scaffold strand were designed to result in complex wireframe and mesh-like objects [55, 56]. Moreover, cross-shaped origami structures tailed by sticky ends on the edges have been used to create long range two-dimensional arrays .
Single stranded DNA tiles containing four domains have been designed to assemble into well-defined nanostructures . The tile is composed entirely of concatenated sticky ends that bind to four local neighbors during self-assembly. Adjacent DNA single stranded tiles connect to each other by pairing up with complementary domains, and continue to form DNA lattices composed of parallel DNA helices. Single strand tile-based approach is an alternative to scaffold DNA-based construction to create larger DNA nanostructures in both 2D and 3D. For example, in the “molecular canvas” strategy (Figure 1E), a pool of DNA strands (single stranded tiles) are designed to connect to each other, forming a rectangular canvas, where each tile serves as a pixel . For a specific shape to be drawn on the canvas, only a subset of tiles corresponding to pixels of the target shape are chosen and annealed to create the desired pattern. This strategy was further expanded to create three dimensional shapes using single stranded “bricks” (Figure 1F) .
Besides, an amount of work has shown that using amphiphilic DNA hybrids (e.g. DNA block copolymers and lipid-DNA) is also an effective approach for the assembly of DNA nanostructures [61-66]. Liu et al. introduced a hydrophobic DNA-surfactant complex in an organic phase for nucleic acid modification and polymerization, producing various amphiphile-DNA nanostructures and DNA side chain polymers. Andreas Herrmann group exploited a DNA tetrahedron with pendant poly (N-isoproylacrylamide) segments for assembling a precisely defined composite nanoparticles .
3 Surface engineering of macrosurface with DNA nanostructures
3.1 1D DNA probes
1D DNA probes are single-stranded DNA (ssDNA) comprising a sequence of at least 15 nucleotides. They are widely used in constructing most DNA sensors and devices due to a lack of secondary structure. The ssDNA with end-tethered thiol can self-assemble onto Au surfaces via the well-known thiol-gold chemistry  with a typical surface coverage of 1011-1013 molecules/cm2. This self-assembly has become a paradigm for the design of DNA recognition layers. Ideally, thiolated DNA is expected to pack well into an ordered monolayer at Au surfaces by a single-point attachment, exhibiting an upright orientation that is favorable for target hybridization. However, in reality, the DNA layer has a rather complicated structure due to the existence of significant interactions between the DNA bases and the Au surface such as electrostatic repulsion between strands, interactions between nitrogen atoms of bases and the Au surface, and strong inter-strand entanglement (Figure 2A) . For example, Herne and Tarlov  discovered that thiolated ssDNA (SH-ssDNA) is not only specifically adsorbed onto the Au via the Au-S bond but also nonspecifically adsorbed via Au-N interactions. Moreover, the discrepancy between the actual thickness of SH-ssDNA monolayer with the expected maximum thickness suggests that the SH-ssDNA monolayer is not tightly packed and that the DNA chains are not oriented perpendicularly to the surface. Grant et al. revealed that the attached DNA could extend further into the solution when repulsive electrostatic fields were applied onto the surface. In addition, several groups discovered that short DNA probes with a high surface density may take upright conformations, which however jeopardizes target accessibility [72, 73].
The ideal configuration for target hybridization is to functionalize the surface with a low density of DNA probes that possess an upright orientation. Tarlov et al. developed a two-step assembly strategy, which involves mercaptohexanol (MCH) passivation that fills the unoccupied space and significantly removes nonspecifically adsorbed DNA (Figure 2B). The DNA probes are projected out into the solution with a favorable upright orientation , owing to the repulsion between the net negative dipole of the alcohol terminus and the negatively charged DNA backbones. This two-step sequential adsorption protocol has been extensively applied in developing various types of DNA-based biosensors and nanodevices . When coupled with signal amplification by enzymes or nanomaterials, highly sensitive DNA sensors with detection limit down to low femtomolar concentrations have been achieved, which allows for the detection of a broad range of pathogens or tumor targets. Pei group designed a stochastic DNA walker powered by exonuclease III, which can autonomously move on a spherical nucleic acid (SNA)-based 3D track (Figure 2C) . By studying the morphological effect of the 3D track on the nuclease activity, they found that the performance of the DNA walker depends on the DNA density and the track conformation. Despite the success of two-step sequential adsorption protocol in improving the surface assembly of DNA as well as the biosensing ability, it remains challenging to eliminate inter-strand interactions owing to the flexible nature of ssDNA. For instance, Ye et al. revealed the existence of many defects of DNA monolayers at Au surface and aggregation patches of DNA using electrochemical atomic force microscopy.
3.2 2D structured DNA probes
It is well-established that ssDNA strands with internal complementary sequences can form secondary structures. This feature can be exploited for constructing pseudo-2D probes in most situations due to their simple structures. In addition, such probes exhibit relatively rigid and ordered structures, which can effectively prevent inter-strand entanglement and thus greatly improve the orderliness of DNA layers at the surface. Accordingly, these 2D structured DNA probes broaden the application in biological analysis.
In 2003, Fan et al. developed a new type of electrochemical DNA (E-DNA) sensor by attaching 2D
DNA probes with a hairpin (stem-loop) structure on Au electrodes. Such E-DNA sensors detect electrochemical signalsbymeansoftarget-inducedconformationalchanges of 2D DNA structures analogous to the optical molecular beacon (MB) approach. The DNA stem-loop structure is tagged with a thiol and an electroactive ferrocene at the 3’ end and 5’ end, respectively (Figure 3A). The 2D hairpin probe then self-assembles onto an Au electrode via the facile gold-thiol chemistry. In the absence of a target, the ferrocene is close to the Au electrode surface, generating redox current. Hybridization with a complementary target sequence results in the opening of the stem and the extension of the loop into a linear duplex. Hence, the distance between the ferrocene and the Au electrode is significantly increased, leading to prominent variations in electron transfer and in turn producing readily measurable changes in electrochemical signals with a detection limit of 10 pM. In contrast to existing electrochemical approaches, this E-DNA sensor allows for sensitive and selective detection of oligonucleotides without the use of exogenous reagents. This E-DNA thus provides a costeffective and efficient technique for reagent-less and reusable detection of picomolar DNA, which holds great potential in medical and military applications. By using the E-DNA scheme, Lai et al. achieved sequencespecific detection of unpurified amplification products of the gyrB gene of Salmonella typhimurium, which may open the path toward effective and field-portable sampleto-answer pathogen identification.
While the initial design of E-DNA sensor was based on a ‘signal-off’ scheme that is susceptible to false-positives, many efforts have been taken to design ‘signal-on’ E-DNA sensors. In 2005, Bockisch et al. developed an alternative ‘signal-on’ sensor for the detection of nucleic acid targets using stem-loop probes, which exploited variation in the steric effect due to hybridizationinduced conformational change. Later, Liu et al. developed an enzyme-based signal-on E-DNA sensor that further increased the sensitivity up to low femtomolar range (Figure 3B). Wei et al. then reported a similar electrochemical sensor that was used to detect mRNA targets with 0.4 fM sensitivity in salivary samples.
An alternative approach is to use detection schemes based on fluorescent DNA sensors. Du et al.[84, 85] developed label-free biological sensors based on fluorescence of DNA hairpins immobilized on metal surfaces. Hybridization efficiency was found to be sensitive to hairpin secondary structure, as well as to the surface distribution of DNA hairpins on the substrate (Figure 3C). Such a sensor can be easily adapted to microarrays and scalable to sensing of different biological molecules.
In a different line of studies, functional nucleic acids with pseudo-2D structures, such as DNA or RNA aptamers and DNAzymes, can also be employed to develop electrochemical sensors for non-nucleic acids targets. For example, Zuo et al. designed an electrochemical sensor for adenosine triphosphate (ATP) by employing an anti-ATP aptamer. The tertiary aptamer structure is stabilized in the presence of the target ATP, which responsively denatures the duplex and releases the complementary DNA. This structural switching brings the ferrocene moiety close to the Au electrode surface, generating measurable electrochemical signals. For a similar purpose, Mirkin et al. developed an aptamer ‘nanoflare’ probe by functionalizing AuNPs with a dense monolayer of nucleic acid aptamers with a high affinity for ATP (Figure 3D). These nanoconjugates can be used for the intracellular quantification of small molecules or proteins in living systems owing to the good cellular uptake ability of AuNPs.
3.3 3D structured DNA probes
Although 2D probes have shown significantly improved biosensing ability compared to 1D probes, it should be pointed out that 2D probes are usually not robust enough to survive on highly crowded surfaces. It is therefore of paramount importance to precisely control the surface density and orientation of grafted DNA probes on the surface to achieve high-performance sensors. 3D DNA nanostructures are expected to address this issue.
In 2010, Pei et al. developed the first 3D DNA structure-based electrochemical sensor by using exquisite tetrahedron-structured DNA probes (TSPs). The TSPs were self-assembled from three thiolated 55-base oligonucleotides and one 80-base oligonucleotide with corresponding complementary regions that fold them into a tetrahedral structure (Figure 4A). The tetrahedron assembly process is extremely fast and efficient with a high yield of ∼85%. This ‘pyramidal’-structured probe is expected to self-assemble onto Au surfaces with a threepoint attachment via the thiol-gold interaction and to leave a pendant probe at the top vertex. Due to the three thiols at the base of the pyramid, TSP is rapidly and strongly anchored at the Au surface within only 2 min, which was monitored in real time by both quartz crystal microbalance and surface plasmon resonance. The surface density was determined as ∼4.8 × 1012 TSP cm-2, corresponding to a probe-to-probe spacing of ∼4 nm.
By employing this DNA nanostructure-based TSP platform, Pei et al. constructed an E-DNA sensor with a conventional sandwich hybridization strategy. The performance of E-DNA sensor was first evaluated by the detection of biotinylated target DNA. The formation of the sandwich pair through the conjugation of avidin-HRP (horseradish peroxidase) with biotin produces intense electrochemical signal via the substrate catalysis of HRP. This non-optimized TSP-based sensor allows for the detection of low picomolar concentrations (∼1 pM), and improves the sensitivity by approximately 250 times compared with that of 1D and 2D probes employing similar HRP-based signal transduction approach. In addition, this TSP-based sensor can sensitively discriminate single-base mismatched DNA, surpassing that of ssDNA probe-based sensors by 25-100 fold in the discrimination factors. Optimization of the TSP-based sensor using interfacial engineering and multienzyme amplification could further improve the sensitivity . For example, Wen et al. employed poly-HRP80, a polymerized streptavidin-HRP conjugate with up to 400 HRP molecules per conjugate, to further amplify the electrochemical signal, which allows for the detection of miRNAs with an ultralow limit of 10 aM, corresponding to ∼600 molecules in 100μL (Figure 4B). It is worthwhile to note that these TSPs provide a promising platform to study DNA hybridization thermodynamics and kinetics with nanometer precision . The detection limit of such DNA sensors can also be programmed and improved by using macroscopic Au electrodes patterned with differently sized TSPs.
The TSP-based surface has proven to be a versatile platform for the detection of virtually any target by programmed configuration of the four edges of the pendant. For example, Pei et al. constructed various TSP-based logic gates (INH, XOR, AND, OR, and half-adder) by incorporating different dynamic sequences into one or two edges. Such logic gates showed sensitive response to a broad range of targets, including protons, metal ions (Hg2+), small molecules (ATP), and complementary DNA strands. In addition to the edges, the pendant probe can also be replaced with different functional nucleic acids for the detection of a variety of biomolecules. For instance, replacement of the pendant probe with an aptamer turns the E-DNA sensor into an immunological sensor for proteins. Pei et al. constructed a thrombin sensor by replacing the top vertex with an anti-thrombin aptamer sequence, which allowed for the detection of thrombin as low as 100 pM. In another example, Wen et al. developed an electrochemical sensor for the detection of cocaine by incorporating a corresponding split aptamer. This sensor exhibited excellent sensitivity toward cocaine, with a detection limit of 33 nM, which is lower than previously reported sensors by three orders of magnitude. In addition, Pei et al. established a highly sensitive and regenerative electrochemical immunological sensor (iTSP sensor) by anchoring DNA-conjugated antibodies on the TSP surface. This TSP surface is well suited for various immunological assays as well as DNA-programmed protein microarrays for proteomic studies. Qu et al.  developed a rapid, DNA nanostructure-supported aptamer pull-down (DNaPull) assay with convective flux in a glass capillary, which allows for analyzing the targets in droplets with nanoliter or picoliter volumes. Moreover, they exploited this DNaPull assay to quantify intracellular ATP level in a discrete number of HNE1 cells to be ⍰3.4 mM (Figure 4C). Additionally, Qu et al. constructed a DNA nanostructured microarray (DNM) with a tubular three-dimensional sensing surface and an ordered nanotopography, and used it for rapid and sensitive multiplexed detection of heavy-metal ions (Figure 4D).
Along a different line, tetrahedral-structured DNA also offers unprecedented opportunities to construct functional plasmonic nanostructures by incorporating
metal nanoparticles (NPs). By positioning four different metal and/or semiconductor NPs in the corners of the tetrahedral-structured DNA, Yan et al. fabricated a family of hetero-particle chiral pyramids with a yield approaching 80%. These chiral pyramids possessed excellent optical activity with g-factors significantly higher than those of traditionally optically active materials and tunable circular dichroism signals in the range of 350–550 nm. Such DNA directional self-assembly approach provides a rapid and high yield synthesis of chiral materials, which might facilitate the applications of chiral materials in life science and metamaterials. Later, Li et al. developed a general strategy for building molecule-like NP architectures (NP-molecule) analogous to the atom-molecule relationship (Figure 4E). The AuNPs are encapsulated into a DNA tetrahedron, which then serve as a guiding agent for further assembly. A rich variety of NP-molecules, such as CH4, SF6, W(CH3)6, and C2H6-like structures have been constructed. Such NP-molecules hold great potential for exploring new nanomaterials with emergent functions that do not belong to the individual component NPs.
3.4 Engineering of nano-surfaces with DNA nanostructures
AuNPs have unique optical and electronic properties, and therefore have shown great potential as a building block for an extensive range of applications that include diagnostics , drug delivery , and plasmonics [100-103]. It is therefore of great interest to create effective DNA recognition layers on the AuNP surface for various applications. Analogous to the functionalization on the macroscopic surface of Au electrode, Song et al. constructed multicolor nanoscale MBs by immobilizing three stem-loop oligonucleotides labeled with different fluorophores on the surface of 15 nm AuNPs (Figure 5A). Three probes labeled with FAM, Cy5 and Rox were designed to target three types of tumor-suppressor genes (exon segments of p16, p21 and p53). Hybridization tests were carried out in solutions spiked with a mixture of three targets, and the nanoscale MBs respond only to the specific target with negligible crosstalk. Since DNA-AuNP conjugates show highly efficient cellular uptake, later Li et al. demonstrated a multicolor fluorescence nanoprobe based on nanoflares, that can simultaneously detect and image three intracellular tumor-related mRNAs in living cells. The fluorescence intensity was found to correlate well with the concentration of tumor-related mRNA in living cells, which provides a useful means to monitor the stage of tumor progression.
Surface functionalization of oligonucleotides is typically carried out via the well-established thiol-gold chemistry. Although this approach has proven to be very useful on the macroscopic surface, it is much more difficult to modulate the orientation and conformation of DNA probes on the surface of AuNPs. Poly adenine (PolyA)-mediated self-assembly strategies have been developed as a promising means for precisely controlling the DNA distribution on the NP surface in a quantitative manner. Whitman et al. first demonstrated the use of PolyA-mediated method for tuning grafting density of ssDNA on a planar Au surface. Their study showed that adenines can preferentially adsorb onto Au surfaces with high intrinsic affinity, making it possible to use PolyA sequences as the anchoring block through multipoint attachment, in contrast to single contact point using thiolated DNA. Based on similar principles, Pei et al. developed a general approach for spatially controlled functionalization of the highly curved surface of AuNPs (Figure 5B). They demonstrated that the multipoint attachment of PolyA block can effectively minimize the nonspecific interactions between other bases and Au, hence pushing the appended block upwards that as a result facilitates DNA hybridization. The lateral spacing and conformation of DNA probes on Au surfaces can also be well-controlled by varying the length of the PolyA blocks. Zhu et al. applied developed polyA-based assembly strategy to investigate the thermodynamics and kinetics of DNA hybridization on gold nanoparticle. They found that the thermodynamic properties are similar to that of duplex in solution and fast hybridization rate is observed with the increasing length of polyA (Figure 5C). This work facilitates constructing high-efficiency and highspeed biosensors for DNA analysis. DNA-AuNP conjugates fabricated using PolyA-mediated method exhibit high and tunable hybridization ability and are therefore well-suited for constructing complex nanostructures and nanodevices . For instance, they constructed a rapid plasmonic sensor for the sensitive detection of DNA. Later, the same group further employed the PolyA-mediated approach for facile assembly of CpG-AuNP conjugates for cost-effective drug delivery, and modulated the immunostimulatory activity of CpG-AuNPs by varying the length of the PolyA block . In another study, Zhao et al. synthesized core-shell gold nanostructures with PolyA-mediated interior nanogaps as SERS nanotags for both the multiplex analysis of DNA markers of diseases and the simultaneous analysis of a variety of bioactive molecules. Recently, by employing the same method, He et al. fabricated a series of core-satellite assemblies, including symmetric Au-Au NPs and asymmetric Ag-Au NP-decorated silicon wafers. The surface density of AuNPs on core NP surface can be systematically modulated by adjusting the length of the PolyA block as well. Their study demonstrated that such core-satellite NPs can serve as high-performance surface-enhanced resonance Raman scattering (SERRS)-based sensing platform for various applications . Similar to PolyA-mediated assembly, Zhu et al. discovered that poly cytosines (PolyC) are also able to mediate the assembly of DNA oligonucleotides on AgNPs  and exploited the unique anisotropic plasmonic scattering behavior of these DNA-AgNP conjugates (Figure 5D).
In addition to ssDNA strands, the assembly of complex DNA nanostructures onto the NP surface has also attracted great attention. Shen et al.  proposed a DNA programmed general strategy for valence-control of QDs in a single step with near quantitative yield (>95%) (Figure 5E). In addition, Lo et al. constructed DNA nanotubes with longitudinally alternating large and small capsules, which can selectively encapsulate AuNPs into the large capsules, producing ‘nanopeapod’ particle lines. These nanotubes can release their NP cargo in response to specific DNA strands, which might find applications in gene-triggered selective drug delivery and biological sensing. Moreover, DNA origami provides more functional sites via staple strand modification and possesses higher rigidity than ssDNA, therefore offering more flexibility in designing complex metal nanostructures. Zhao et al. demonstrated the application of spatially addressable DNA origami nanocages to encapsulate AuNPs of various sizes (Figure 5F). The encapsulation efficacy was found to decrease with larger AuNPs due to the severe deformation when accommodating 15 nm AuNPs. More significantly, the programmability of the DNA origami cages provides a promising opportunity to interrupt the symmetry of spherical NPs and allows for the complex spatial arrangement of AuNPs.
3.5 Surface engineering of live cell with DNA nanostructures
While the utilization of DNA nanostructures in biosensors and nanodevices has been extensively explored in the past few decades, their applications in diagnostics and therapeutics in living systems are beginning to emerge. In 2010, Walsh  and Li  independently discovered that DNA tetrahedron can cross the cellular membrane without the aid of transfection reagents. The DNA tetrahedron showed high resistance toward nuclease degradation and remained substantially intact within cells for at least several hours . Given the noncytotoxic nature and hollow structure of DNA tetrahedron, it holds
great potential for applications in cellular imaging and targeted drug delivery. For example, Pei et al. designed a series of 3D DNA nanostructure-based logic gates using tetrahedral DNA nanostructures and applied the logic operations for in vivo sensing and imaging of ATP in living cells (Figure 6A). The controllable shape of tetrahedron also offers a useful means to logically control drug release in cells. By appending unmethylated CpG motifs to the tetrahedron, Li et al. demonstrated that functional tetrahedrons can be applied as a new type of noninvasive delivery system for CpG oligodeoxynucleotides (ODNs). The DNA tetrahedral nanostructures were found to significantly increase the efficacy of CpG ODNs without sacrificing biocompatibility. Another work reported by Lee et al. constructed DNA/siRNA tetrahedral nanostructures using six ssDNA strands and six doublestranded siRNAs for targeted delivery in vivo. The design of such DNA nanostructures allows for full control over the nanostructure size, spatial orientation of the siRNA, and the locations and density of cancer-targeting ligands, which provides a useful means to develop highly efficient, long-lived and target-specific nanocarriers for delivering therapeutics into living systems. Interestingly, they found that at least three folate ligands per tetrahedron are required for optimal delivery of the siRNAs into cells, and gene silencing efficacy can be dramatically affected by the orientation and location of ligands. A variety of different DNA nanostructures have also been exploited for in vivo applications. For example, Modi et al. constructed a DNA nanomachine called the I-switch, which shows response to protons and functions as a pH sensor based on fluorescence resonance energy transfer (FRET). They then demonstrated the operation of this pH-triggered DNA nanomachine for mapping spatial and temporal pH changes associated with endosome maturation in live cells. Later, the same group demonstrated that this synthetic DNA nanomachine can also function autonomously in a multicellular living organism, which provides a powerful tool to interrogate complex biological phenomena (Figure 6B) .
DNA nanostructures also provide a very powerful approach to control cell behavior, including cell adhesion, cell orientation, cell motility, and intracellular signaling pathways, through the nanoscale engineering of cell surface interface. It has been demonstrated that cells are inherently sensitive to local mesoscale, microscale, and nanoscale patterns of chemistry and topography . In 2006, Chandra et al. reported a novel strategy for engineering cell adhesion events by employing a DNA-based approach. ssDNA was attached to the plasma membranes of living cells, and upon hybridization with complementary sequences tagged on the materials surfaces, cells can be captured and patterned into arrays. This DNA-based approach offers the ability to engineer cells to a much higher level of complexity than traditional approaches typically involving the cell’s natural repertoire of adhesion receptors, such as laminin or RGD peptides [126, 127]. By exploiting this method, they demonstrated the formation of complex cell patterns , the capture of single cells for gene expression analysis (Figure 6C) , and the attachment of living cells to AFM tips for force measurement . Later, the same group improved this technique by using NHS-DNA conjugates, which allows for capturing many new types of cells that are generally incompatible with integrin-targeting approaches, and significantly shortens the processing time to less than 1hr . Similarly, by exploiting the hybridization between DNA-coated cells (Figure 6D), the same group demonstrated the bottom-up synthesis of microtissues composed of multiple cell types with programmed connectivity . They then constructed a paracrine signaling network in these isolated artificial 3D microtissues. In addition to patterning cells, another study reported by Coyle et al. has shown that a DNA-based strategy can also be used to mediate the assembly of proteins into defined heterodimers or higher-order oligomers on supported membranes, which can then be used to direct the molecular composition of cell membrane receptor clusters. Moreover, instead of using simple ssDNA strands, Langecker et al. used scaffolded DNA origami to create lipid membrane channels composed of a stem that penetrated and spanned a lipid membrane, as well as a barrel-shaped cap that adhered to the membrane (Figure 6E). They have demonstrated that such synthetic channels can be used to discriminate single DNA molecules.
4 Conclusion and outlook
This review summarizes the unique properties of DNA nanostructures including strong capability for biomolecular recognition on the bio-surface, and such rationally designed DNA nanostructures show innovative applications in biosensing for analysis of various proteins, nucleic acids, and small molecules. Moreover, DNA nanostructures with good permeability present well controlled logical responses to environmental stimuli, which allows for their use in drug delivery. Hence, it is possible to achieve in vivo diagnosis and controlled release of drugs by taking advantage of DNA-based nanocarrier systems with embedded intelligent sensors. Given its versatility, it is envisioned that DNA nanostructures hold great promise as a solid tool in theranostics.
This work was supported by the National Science Foundation of China (grant numbers 21722502, 21505045, 21705048), the Shanghai Pujiang Talent Project (16PJ1402700), China Postdoctoral Science Foundation (2015M581565, 2017T100283).
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