DNA Nanocages - Chemistry of Materials (ACS Publications)

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DNA Nanocages Arun Richard Chandrasekaran, and Oksana Levchenko Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.6b02546 • Publication Date (Web): 18 Jul 2016 Downloaded from http://pubs.acs.org on July 23, 2016

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Chemistry of Materials

DNA Nanocages Arun Richard Chandrasekaran* and Oksana Levchenko The RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA. ABSTRACT: DNA has been used in the construction of a variety of nanoscale structures. Of these, designed cage-like structures of sizes ranging from ~10 nm to ~100 nm and molecular weights of up to ~60 MDa have been developed. These nanocages have been assembled using different strategies that include one-pot approach, modular assembly, hierarchical self-assembly and the DNA origami technique. Such structures can be programmed to be reconfigurable via external triggers such as ligands, biomolecules and pH. These objects provide a route to encapsulate proteins and nanoparticles, and allow targeted delivery of these guests. With such versatile properties, DNA nanocages find applications in medicine, biotechnology, imaging and materials science.

1. INTRODUCTION The emergence of nanotechnology has contributed to the creation of novel materials for chemical, biological and materials science applications. Of these, DNA has been shown to be extremely versatile and highly programmable for the self-assembly of nanoscale structures.1-3 Some of the main features of DNA4 that make it suitable for nanoscale construction are as follows: (i) the DNA duplex is inherently a nanoscale material with a diameter of ~2 nm and a helical pitch of ~3.4-3.6 nm, (ii) a persistence length of ~50 nm, thus serving as a rigid building block for self-assembly, (iii) the canonical Watson-Crick base pairing in DNA (A:T and G:C) provides a predictive molecular self-assembly pathway, and (iv) single-stranded overhangs (sticky ends) can be used to connect duplexes providing a route to hierarchical assembly. Furthermore, various enzymes such as polymerases and nucleases can be used to manipulate DNA. These features, as well as the ability to synthesize DNA strands with any desired sequence of bases with multiple chemical modifications, have allowed DNA to be used for rationally designing various nanostructures. One of the main uses of DNA is in the construction of one-5-7, two-8-10 and threedimensional (3D) arrays11-13 that are useful as a framework for the organization of nanoparticles14-15 and biomolecules.16-17 In addition, DNA nanostructures have been utilized in applications such as nanoelectronics,18-19 biomolecular computation,20-21 cellular imaging,22 biosensors23-24 and in the creation of enzyme cascades.25-26 One of the most alluring applications of DNA nanostructures is the encapsulation of external moieties for biologically targeted delivery and subsequent triggered release of therapeutics. For this purpose, DNA nanocages of varying shapes and sizes with different functionalities have been developed. The advantage of using DNA cages is that they can be functionalized with a multitude of chemical tags for target attachment.27 Moreover, nanostructures made using

DNA exhibit enhanced stability, biocompatibility and cellular permeability making them suitable for both in vitro and in vivo applications.28-29 Here, we discuss the different strategies used to construct DNA cages, and their applications in encapsulating proteins and nanoparticles, targeted delivery, in vivo imaging and in materials science. 2. CONSTRUCTION OF DNA CAGES A variety of DNA nanocages — with cavity sizes ranging from ~10 nm to ~100 nm and molecular weight of up to ~60 MDa — have been constructed over the past three decades. Figure 1 shows a timeline of various DNA nanocages developed over the years. These structures vary in complexity from containing simple double helical edges with hollow faces to complex closed structures with multiple crossover sites on each edge. Some examples include cubes (Figure 1i),30-31 truncated octahedron (Figure 1-ii),32 octahedra (Figure 1-iii),33-35 tetrahedra (Figure 1-iv),36-39 dodecahedra (Figure 1-vi),37 trigonal bipyramids,40 icosahedra (Figure 1-vii),41 truncated icosahedra,42 prisms (Figure 1-xiii),43 and buckyballs (Figure 1-vi).37 Evolving in complexity, hybrid DNA motifs with synthetic linkers at the vertices have been used to construct prisms (Figure 1-v)44-45 and a dodecahedron.46 In addition, the DNA origami technique47 has been used to construct larger structures such as a tetrahedron (Figure 1x),48 a DNA box (Figure 1-ix)49 and DNA spheres and flask (Figure 1-xii).50 The strategies for creating such nanocages overlap on the use of some basic design rules and are discussed here in four broad categories: (i) modular self-assembly, in which multiple components that form part of the object are created first, followed by assembly into the target DNA nanostructure; (ii) hierarchical assembly of branched DNA tiles, in which a specific DNA tile connects via sticky end cohesion into higher order DNA structures; (iii) one-pot

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Figure 1. Developmental timeline of DNA cages. (i) Cube30 (ii) truncated octahedron32 (iii) octahedron33 (iv) tetrahedron with 2turn edges36 (v) prisms44 (vi) polyhedra assembled from 3-point star motif37 (vii) icosahedron41 (viii) metallated triangular prisms45 (ix) box with lid. Reproduced with permission.49 Copyright 2009, Nature Publishing Group (NPG) (x) origami-tetrahedron48 (xi) origami-based wireframe tetrahedron with hinges57 (xii) origami sphere and flask. Reproduced with permission.50 Copyright 2011, American Association for the Advancement of Science (AAAS) (xiii) minimal prism using only two component strands 43 (xiv) origami-based larger polyhedra assembled from DNA tripods58 (xv) complex origami-based wireframe structures. Reproduced with permission.61 Copyright 2009, NPG.

approach, in which the cages can be built by annealing together a mixture of oligonucleotides; and (iv) DNA origami-based strategy, in which a long single stranded scaffold is folded into the desired cage structure by the addition of short complementary staple strands. 2.1. Modular assembly Some of the earliest DNA nanostructures involved complex steps to create the components of the target structure. One such example is a cube, the first 3D object constructed from DNA, with twelve edges comprising of two doublehelical turns each, arranged around eight vertices.30 This construction process involved cyclization of some of the component strands, followed by hybridization, purification and a final ligation step to create a closed structure with the topology of a cube (Figure 2A-i). A more complex polyhedral structure, with the connectivity of a truncated octahedron, was later constructed using solid-supportbased assembly.32 This structure contained six square and eight hexagonal faces formed from 36 edges connected around 24 vertices (Figure 2A-ii). Another example is an octahedron formed by simple denaturation-renaturation

of a 1669-nucleotide (nt) single-stranded DNA and five synthetic 40-nt DNA strands.33 This structure contained 12 edges, joined by six four-way junctions to form a hollow octahedron, ~22 nm in diameter (Figure 2A-iii). The edges of this structure were designed to contain different DNA sequences and provide uniquely addressable points for attachment of sequence-specific cargoes. Another polyhedral cage, a DNA icosahedron (Figure 2A-iv) has been constructed by a modular assembly strategy.41 The two halves of the icosahedron were first assembled from three distinct, pre-folded five-way-junctions,51 and were then assembled into an icosahedron through the interaction of programmed sticky ends. These icosahedra are effective nanocapsules to retain guests within the cage, and can be used for targeted cargo delivery (discussed in section 4.2). This strategy can also be extended to build larger and more complex icosahedra for encapsulating different guest molecules. Another example of stepwise assembly is a multi-layered structure consisting of different sized tetrahedra (Figure 2A-v).52 The inner tetrahedron was constructed using a three-point-star motif,37 and double crossover (DX) connecting tiles were used for the outer


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Figure 2. Strategies for construction of DNA cages. (A) Modular assembly of DNA cages. Top: Example shown is the assembly of a DNA icosahedron.41 Bottom: (i) DNA cube,30 (ii) truncated octahedron32 (iii) octahedron33 (iv) icosahedron41 (v) multilayered tetrahedron52 (vi) triangular prism.45 (B) Tile-based hierarchical self-assembly of DNA cages. Top: Example shown is the hierarchical assembly of a DNA tetrahedron from 3-point-star motifs.37 Bottom: (i) A three-point-star motif that can self-assemble via sticky end cohesion into a tetrahedron, dodecahedron or bucky ball 37 (ii) a five-point-star motif self-assembles into a DNA icosahedron42 (iii) control over symmetry of component tiles allows for the self-assembly of a cube.31 (C) One-pot assembly of component strands into DNA cages. Top: Example shown is the cooperative assembly of a DNA tetrahedron from four component strands.36 Bottom: (i) A DNA tetrahedron created from four oligonucleotides36 (ii) A trigonal bypramid40 (iii) Various prisms containing organic material at the vertices44 (iv) Minimal construction of DNA prisms using only two DNA strands.43 (D) DNA origami-based cages. Top: Example shown is the formation of a DNA origami tetrahedron.48 Bottom: (i) a tetrahedral container48 (ii) a box with a controllable lid49 (iii) an octahedral frame56 (iv) a hinged tetrahedron57 (v) wireframe DNA polyhedra58 (vi) an Archimedean solid cuboctahedron61 (vii) a snub cube.61 Reproduced with permission.36, 40, 43-44, 49, 52, 54, 56, 58, 61 Copyright 2005 AAAS, 2007 American Chemical Society (ACS), 2013 The Royal Society of Chemistry (RSC), 2007 ACS, 2009 NPG, 2015 ACS, 2009 NPG, 2015 NPG, 2014 AAAS, 2015 NPG respectively.

tetrahedra. In addition, each layer contained precisely positioned single-stranded tails that can hybridize to each other forming a duplex bridge connecting adjacent layers. Such assemblies demonstrate the high complexity of DNA cages that can be built.

Triangular DNA motifs, connected by specific linker strands, have been used for assembling 3D prisms (Figure 2A-vi).45 The vertices of these structures contained bis-2,9diphenyl-1,10-phenanthroline (dpp) ligands that allow sitespecific metal binding. Use of metal-DNA junctions en-


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hanced the overall stability of these nanostructures in resisting denaturation and provides a route to obtaining higher yields of stereospecific DNA-nanostructures.35,53 In addition, metallation of 3D DNA cages allows for a variety of different activities including redox, photochemical or magnetic switching of pore sizes, catalytic activity on the encapsulated molecules, and luminescence sensing. Such an approach can also be extended to the construction of 3D DNA nanotubes54 with potential use in the growth of nanowires and the encapsulation of guest molecules, specifically for the purpose of “catch and release” of cargo. 2.2. Tile-based hierarchical assembly The concept of using DNA as a building material arose from the notion that specifically designed DNA motifs can self-assemble via programmable interactions (eg: sticky end cohesion) into higher-order structures. DNA motifs have been designed for hierarchical assembly of 3D cages of various topologies and sizes. For example, a three-pointstar motif (Figure 2B-i) has been used to create tetrahedra, dodecahedra, or buckyballs by controlling the flexibility and concentration of the component tiles.37 Each arm of these star-shaped DNA motifs is a four-arm junction and can self-assemble into symmetric DNA polyhedra through sticky end hybridization. These polyhedra can also be reconfigured to open and close for the encapsulation and release of various guests (discussed in section 4.1). This strategy can be expanded to create more complex polyhedra by using DNA motifs with more arms. One such example is the five-point-star motif that has been used to construct a DNA icosahedron (Figure 2B-ii).42 Furthermore, by controlling the symmetry of such DNA motifs, the face geometry of self-assembled DNA polyhedra can be precisely tailored. For example, a DNA cube has been constructed using eight identical copies of the three-point-star motif (Figure 2B-iii).31 These motifs are identical when in solution, but bend in opposite directions when assembled into the cube. This occurs because the motifs are separated by an odd number of helical turns between them, leading to the formation of the desired cage configuration. 2.3. Assembly of individual strands DNA cages have been constructed in a one pot reaction by direct assembly of component combination of DNA strands. The first example is a DNA tetrahedron that was designed to self-assemble in a single step by annealing individual oligonucleotides (Figure 2C-i).36 Each edge of this tetrahedron comprises two double-helical turns of DNA, and can be reconfigured to reversibly change its shape in response to specific molecular signals (discussed in section 4.1).55 This type of cooperative assembly scheme developed for DNA tetrahedra can also be extended to larger polyhedra. A complex, less symmetric, trigonal bipyramid (Figure 2C-ii) has also been created by one-step assembly.40 Single step assembly of more complex polyhedra will lead

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to robust assembly in three dimensions for use as molecular building blocks and cages. A DNA dodecahedron has been constructed using trisoligonucleotides.46 A regular dodecahedron consists of twelve regular pentagonal faces, with three meeting at each vertex to give 30 edges and 20 vertices. In this case, the centers of the trisoligonucleotides represent the vertices, and the edges are formed by hybridization of complementary strands of proximate trisoligonucleotides. In addition, DNA prisms have been assembled from single stranded cyclic DNA constructs containing organic material at the vertices that were connected using linking strands and rigidifying strands (Figure 2C-iii).44 Although the starting material involves preformed cyclic DNA strands with organic vertices, the formation of the DNA prisms entails a single step assembly of all the components. Based on the number of vertices incorporated into the DNA rings (triangle with 3 vertices, square with 4, pentagon with 5, etc), the structures can assemble into a triangular prism, a cube, pentameric prism, hexameric prism, and so on. Using these simple building blocks, more complex structures such as a “heteroprism” and “bi-prism” have also been constructed. Such a method allows for the construction of 3D cages with minimal procedures and materials. In addition, these constructs can also be modified to respond to specific external stimuli (discussed in section 4.1). 3D DNA nanoprisms have also been constructed using a symmetric design strategy that involved only two different DNA strands (Figure 2C-iv).43 Such a strategy does not require chemically modified DNA or multiple strands, thereby minimizing the cost and complexity. 2.4. Origami-based assembly Cages constructed using individual strands and tiles are limited to ~5 MDa. The DNA origami technique42 has been used to construct DNA cage structures as large as 60 MDa. One example of a DNA origami-based structure is a tetrahedron with ~54 nm edges48 and an internal cavity of 1.5 × 10-23 m3 (Figure 2D-i). Hybridization of the scaffold and staple strands resulted in planar triangular faces that closed on each other to form the tetrahedron. A similar strategy was used to fold six connected DNA sheets into a nanoscale DNA box (Figure 2D-ii).49 Moreover, the lid of the DNA box was functionalized with a lock and key mechanism based on toehold-mediated strand displacement. Such dynamic cage structures that operate under native conditions allow the packaging of biologically active components and provide a route to the creation of 'sense and act' structures. An origami-based octahedral frame has been constructed for designed positioning of nanoparticle clusters.56 This octahedron contained six vertices pre-programmed with sticky ends that can bind DNAfunctionalized gold particles (Figure 2D-iii). By altering the sticky end sequences on the vertices, the octahedral frame can be designed to bind different clusters, making it


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Figure 3. DNA cages for the encapsulation of biomolecules. (A) DNA polyhedra for streptavidin immobilization (shown are a tetrahedron, octahedron and icosahedron). Reproduced with permission.62 Copyright 2012. Wiley-VCH. (B) Encapsulation of cytochrome c in a DNA cage.63 (C) DNA tetrahedron for the encapsulation of transcription factor catabolite activator protein. Reproduced with permission.64 Copyright 2013 Wiley-VCH. (D) PNA linkers for attaching proteins cytochrome c and azurin in a DNA tetrahedron. Reproduced with permission.67 Copyright 2014 ACS.

useful for creating heterogeneous clusters. These octahedra were also used as interparticle linkers for the creation of programmed 1D and 2D arrays with specific arrangement of the particles. Another example is a hollow, rigid tetrahedron with a 75 nm edge (Figure 2D-iv) constructed using DNA origami.57 This structure was designed to contain single stranded hinges at each of the vertices, thereby providing structural variability while also providing sitespecific attachment of dye and/or linker molecules at unique positions on the edges.

to the creation of more complex functional materials. Another example is a snub cube (Figure 2D-vii), an Archimedean solid with 24 vertices made of 5 x 4 junctions and 60 edges of 5-turn double DNA duplex, comprising 38 faces.61

Hierarchical self-assembly of DNA polyhedra has also been achieved using DNA origami (Figure 2D-v).58 The basic unit in this case was a DNA origami tripod motif that could assemble into a variety of polyhedra by controlling the angles and arm lengths of the motif. These include a tetrahedron (20 MDa), a triangular prism (30 MDa), a cube (40 MDa), a pentagonal prism (50 MDa), and a hexagonal prism (60 MDa). The use of multicomponent origami structures allows the construction of very large polyhedra, with sizes comparable to that of bacterial microcompartments such as carboxysomes. This design strategy can be extended to n-arm (n ≥ 4) branched motifs with controlled inter-arm angles for the construction of more sophisticated polyhedra. Moreover, enclosing such structures in lipid membranes59 make them potentially useful as bioreactors or as drug delivery vehicles. The design of wireframe structures37,60 using DNA origami was recently extended to the construction of highly complex and programmable finite nanostructures.61 One example is an Archimedean solid cuboctahedron with 12 vertices and 24 edges (Figure 2D-vi). Each vertex is a 4 × 4 junction and each edge is a 14-turn-long double DNA duplex. Such architectures lead

Star-shaped DNA motifs that self-assemble into DNA polyhedra37 (discussed previously in section 2.2) have been used to immobilize streptavidin (STV) within their cavities.62 This was achieved by incorporating a biotin group at the 5' end of one of the component DNA strands. Upon self-assembly of these motifs, each face of the DNA polyhedra displayed three biotin moieties that were used to bind STV (Figure 3A). Such trivalent binding reduces the freedom of the bound STV relative to the DNA scaffold providing controllable guest freedom in DNA-directed guest organization. In addition, the DNA tetrahedron based on the three-point star motif was also used to encapsulate an antibody.62 In this case, one of the component strands was modified to contain a fluorescein antigen instead of biotin, which was used to recruit anti-fluorescein antibody to specific locations on the tetrahedron.

3. DNA CAGES AS HOSTS FOR EXTERNAL GUESTS 3.1. Encapsulation of proteins and antibodies

A smaller DNA tetrahedron36 (discussed in section 2.3) has been used to encapsulate the protein cytochrome c (Figure 3B).63 The protein was conjugated to one of the component strands via a surface amine before assembly of the tetrahedron. Formation of the tetrahedron with the


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Figure 4. DNA cages for the encapsulation of nanoparticles. (A) DNA-AuNP core-shell nanostructures based on a DNA tetrahedron, octahedron and icosahedron. Reproduced with permission.68 Copyright 2014 ACS. (B) Nanoparticle clusters of defined orientations created using DNA polyhedra. Reproduced with permission.69 Copyright 2015 ACS. (C) A DNA origami container for dictated assembly of AuNPs within a cavity. Reproduced with permission.73 Copyright 2011 Wiley-VCH. (D) A DNA origami box for the encapsulation of exactly one AuNP. Reproduced with permission.74 Copyright 2015 NPG.

DNA-protein conjugate resulted in the protein being encapsulated within the tetrahedron. Such a DNA cage has also been used to encapsulate the transcription factor catabolite activator protein (CAP)64 by modifying one of the edges to contain the CAP binding site.65 CAP binds to the tetrahedron edge in the presence of its allosteric effector cyclic adenosine monophosphate (cAMP).65-66 Encapsulating CAP within the cage renders it inactive, which inhibits it from binding cellular DNA. However, the cage can be opened using DNA nuclease I, releasing, and thus activating the transcription factor (Figure 3C). Cages with such triggered conformational changes can be used for highly controlled protein release systems in vivo, leading to efficient drug delivery systems and theranostic tools. In another example, a PNA linker was used to encapsulate two small proteins, cytochrome c (12.5 kDa) and azurin, (14 kDa) into a tetrahedral DNA nanocage (Figure 3D).67 Following conjugation of the PNA strand to the proteins through a surface thiol, the PNA-protein conjugate was bound to a complementary single stranded region on one of the edges of the tetrahedron. This design could be expanded to connect up to 4-6 polypeptides on adjacent edges of the DNA nanocage by introducing the appropriate PNA binding sequences. The ability to systematically introduce different proteins into defined locations within such a three dimensional structure may facilitate investigations of protein-protein interactions under physiological conditions.

3.2. Encapsulation of nanoparticles Encapsulation of gold nanoparticles (AuNPs) in polyhedral DNA nanocages have led to the formation of core-shell structures (Figure 4A).68 DNA polyhedra based on the three-point star motif37 were designed to contain single stranded extensions within the cage. These strands were complementary to the single strands conjugated to AuNP thereby encapsulating the AuNPs via DNA hybridization. One advantage of this kind of assembly is that confinement of the AuNPs in these cages restricts the spherical symmetry of the DNA-AuNP conjugates, causing them to adopt well-defined bonding directions based on the DNA polyhedral symmetry. For example, when encapsulated in a DNA tetrahedron, a DNA-AuNP can only interact with other DNA-AuNPs (via ssDNA hybridization) through the four faces of the tetrahedron because of both electrostatic repulsion and steric hindrance. Furthermore, such DNA cages also allow controllable release of the AuNP guest, pointing to potential applications in delivery using DNA nanocages (discussed in section 4.3). Other modular strategies have been developed41 to encapsulate nanoparticles without covalently linking them to the component strands of the DNA cage. Such DNA cages can also be used to host nanoparticle clusters (NP-molecules) with defined compositions.69 A series of NP-molecules assembled using this strategy include a one-core, five-NP, CH4-like structure (with a tetrahedral symmetry); a one-core, seven-NP, SF6-like structure (with


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an octahedral symmetry); a one-core, seven-NP, W(CH3)6like structure (with a trigonal prismatic symmetry); and a two-core, eight-NP, C2H6-like structure (with a D3 symmetry) (Figure 4B). These materials exhibit emergent properties that depend not only on the chemical identities of the individual NPs, but on the spatial organization of the NPs as well.70 Similar strategies can be applied to other inorganic particles, such as quantum dots71 and magnetic nanoparticles,72 leading to the synthesis of new programmable materials with tailored functions.

thus forming a triplex that holds the connection between the tiles forming the tetrahedron. In neutral pH, the cytosines are no longer protonated, resulting in weaker sticky ends without triplex, which leads to the breakdown of the tetrahedron into its component tiles (Figure 5D).

Nanocages created using DNA origami have also been used to encapsulate nanoparticles. For example, a DNA origami cage based on honeycomb lattice design with inner cavity dimensions of 10 nm X 10 nm has been used to encapsulate AuNPs.73 The particles were specifically positioned within the cavity of the DNA cage by modifying the inner surface of the cavity to contain capture probes that are complementary to the single stranded DNA on DNAAuNP conjugates (Figure 4C). These cages offer site-specific placement of DNA conjugates and can be used as platforms for engineering bioinspired materials. Another example is the box-shaped DNA origami that was used to encapsulate exactly one 10 nm AuNP.74 In this case, a thiolmodified AuNP was attached to the inside face of the 'open form' of the box and the box was then closed using additional DNA strands (Figure 4D). 4. APPLICATIONS OF DNA CAGES 4.1 Reconfigurable DNA cages Reconfigurable nanostructures are useful for triggered release of encapsulated guests. For this purpose, several DNA cages have been designed to reconfigure in response to external stimuli such as ligands, additional DNA strands, and pH. In addition, the functionality of these DNA cages can also be switched. For example, the surface porosity of a DNA tetrahedron could be reversibly changed by a capping motif via DNA hybridization and strand displacement (Figure 5A).75 The shape of pre-formed DNA tetrahedra can be changed in response to specific molecular signals.55 By adding a fuel strand, the shape was changed from a closed state with a shorter edge (~6.8 nm) to an open state with a longer edge (~10.2 nm) (Figure 5B). This process can be reversed by toe-hold-based displacement of the fuel strand by the addition of a complementary antifuel strand. Fabrication of DNA cages with such shape-changing abilities opens new avenues for dictated assembly and release of guest molecules. Another example of reconfigurable cages is the oscillating 3D prism44 with interchangeable cavity sizes (Figure 5C). The edges of the prism were designed to contain a hairpin. Addition of a fully complementary strand opens the hairpin leading to the formation of longer double-stranded edges, thereby expanding the encapsulation volume. A DNA tetrahedron has been re-engineered to open and close reversibly via triplex interactions in the sticky ends.76 In acidic pH, the cytosine in the sticky end is protonated,

Figure 5. Reconfigurable DNA cages. (A) A DNA tetrahedron with switchable surface porosity triggered by strand displacement. Reproduced with permission.75 Copyright 2012 ACS. (B) A shape-changing DNA tetrahedron based on the addition of fuel and antifuel DNA strands. Reproduced with permission.55 Copyright 2008 NPG. (C) An oscillating DNA prism with flexible capsule size. Reproduced with permission.44 Copyright 2007 ACS. (D) A smart DNA tetrahedron that is intact at low pH and breakdowns at neutral pH.76

4.2. Dynamic cages for triggered cargo release Programmable DNA nanostructures provide control over structural transitions and are especially useful for triggered release of encapsulated cargo. One classic example is the DNA origami box discussed in section 2.4. The lid of the box can be locked or opened using additional DNA strands (Figure 6A).49 Such structures allow for selective encapsulation and release of molecules aiding in therapeutic drug and biomolecule delivery. DNA polyhedra can be designed to deliver a molecular payload in response to specific signals with both spatial and temporal control. One such example is the controlled opening of a DNA icosahedron loaded with fluorescent dextran in response to the addition of cyclic-di-GMP (cdGMP).77 The DNA icosahedron was formed by assembling the top and bottom halves via sticky end cohesion. In this case, the top half of the cage was integrated with chemically responsive cdGMP aptamers. Addition of cdGMP resulted in aptamer remodeling leading to dissociation of the icosahedron into its two constituent halves via strand displacement. This structural change caused the release of the encapsulated fluorescent dextran (Figure 6B). Such chemically induced release strategies are applicable to other DNA polyhedra as well


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and are useful for controlled release of molecular cargo to specific cells in living organisms.78 Figure 6. DNA cages for triggered release of guests. (A) A DNA box that can be opened or closed by additional DNA strands. Reproduced with permission.49 Copyright 2009 NPG. (B) A DNA icosahedron that releases fluorescent dextran upon addition of cdGMP. Reproduced with permission.77 Copyright

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manipulate the cage to open or close in response to temperature change. At lower temperatures (< 22 °C), the hairpin sequence folded on itself causing the cage to be in the closed conformation with a smaller cavity size, thereby preventing the enzyme from entering. Increasing the temperature to 37°C induced the hairpin to unfold into the open conformation of the cage allowing entry to the enzyme. This feature enabled the capture or release of cargo at 37 °C, while retaining the cargo in the central cavity of the cage at 4°C (Figure 6C). Moreover, the entrapped enzyme was shown to retain its catalytic activity during the encapsulation/release process. Apart from biomolecules such as proteins, nanoparticles can also be controllably released from DNA cages. For example, AuNPs encapsulated in DNA cages were released by the addition of DNA strands that were fully complementary to the DNA part of the DNA-AuNP conjugates.68 Upon hybridization of the additional DNA strands with those on the DNA-AuNP conjugates, the DNA tails of the DNA cages were displaced, resulting in the release of AuNPs (Figure 6D). 4.3. DNA cages as drug carriers

2013 Wiley-VCH. (C) A temperature-controlled DNA cage for capture and release of the enzyme horseradish peroxidase. Reproduced with permission.79 Copyright 2013 ACS. (D) AuNPencapsulating DNA tetrahedron that can release its cargo upon addition of DNA strands complementary to that on the DNA-AuNP conjugates.68

Release of encapsulated guests can also be triggered using temperature, as was demonstrated using a preassembled and covalently closed truncated octahedron that encapsulated horseradish peroxidase enzyme.79-80 A hairpinforming sequence attached to one of the edges was used to

3D cages based on DNA have potential as smart delivery devices for molecular cargo in living systems. For example, proteins have been encapsulated in a clam-shell-like DNA origami nanostructure that can be opened or closed using aptamer-antigen interactions.81 The structure was designed as a hexagonal barrel with the top and bottom halves connected in the rear via scaffold strand hinges (Figure 7A). The front end of the barrel was designed to contain two DNA aptamers that can bind to partially complementary strands holding the two halves in a closed position. In the presence of the correct aptamer antigen, the aptamer strand dissociates from the complementary strand and binds to the antigen causing the cage to open. The inside of the origami cage was modified to contain cargo-binding sites, allowing the encapsulation and delivery of a wide variety of biological moieties. Moreover, these containers can be targeted onto specific cells by tagging them with cell-specific aptamers. Similar nanorobots have been designed to generate logical outputs that can control the release of molecular payloads in living cockroaches (Figure 7B).82 DNA nanostructures hold potential to be explored for vaccine development because of the control over particle size, shape, and epitope valency. Tetrahedral DNA nanostructures have been used as a scaffold to assemble a model antigen, phycoerythrin-conjugated streptavidin (PE-STV), and an adjuvant, CpG oligo-deoxynucleotides, into a synthetic vaccine complex (Figure 7C).83 The immunogenicity of the fully assembled tetrahedron-STV-CpG vaccine complexes were found to induce a higher level of


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Figure 7. DNA cages for drug delivery. (A) A logic-gated nanorobot for delivery of molecular payloads.81 (B) Designed nanobots for release of cargo in cockroaches.82 (C) A DNA tetrahedron-based synthetic vaccine complex.83 (D) A CpG loaded DNA tetrahedron for enhanced immunostimulation.85 Figures adapted with permission.2 Copyright 2014, ACS.

anti-STV IgGs compared to those of an unassembled mixture of STV and CpG, or STV alone. Moreover, assembly of multiple adjuvant elements on DNA nanostructures has shown increased immunostimulation in vitro84-85 and ex vivo.86 Such DNA scaffolds will be useful in constructing antigen-adjuvant complexes that elicit a strong and specific antibody response in vivo without inducing an undesirable response against the scaffold itself. In another example, functional, multivalent DNA nanostructures have been developed by adding unmethylated CpG motifs to DNA tetrahedra.85 These structures induced immunostimulatory effects and resulted in enhanced secretion of various pro-inflammatory cytokines. Moreover, these nanostructures exhibited high efficacy and were shown to be nontoxic. DNA cages such as these have been found to remain substantially intact within the cells for at least 48 h after transfection87 and can enter cultured mammalian cells effectively, both with and without the aid of a transfection reagent. DNA tetrahedra have also been used to deliver small interfering RNAs (siRNAs) into cells to silence target genes in tumors (Figure 7D).88 Each edge of the tetrahedron contained a nick and an overhang that was complementary to part of the siRNA strands thus allowing six siRNA strands to be bound to one tetrahedron. Use of the DNA tetrahedron provides programmable size, orientation and density of the bound ligands. This system was used for targeted delivery to cancer cells by conjugating cancer-targeting ligands (peptides and small molecules) to induce gene silencing. In addition, these ligandconjugated DNA cages exhibited higher blood circulation time in comparison to just siRNAs. In addition, aptamerconjugated DNA icosahedral structures have been used to carry doxorubicin for cancer treatment.89 This system showed efficient internalization of the nanostructures and also allowed controlled release based on environmental pH.

4.4. DNA cages for cellular imaging DNA polyhedra have been used as hosts for encapsulating functional cargo such as a fluorescent biopolymer fluorescein isothiocyanate (FITC)-Dextran (FD).78 FD is pH sensitive and allows for the measurement of organellar pH inside living cells and whole organisms.90 The functionality of this host-cargo complex was demonstrated in vivo by quantitatively mapping pH changes associated with endosomal maturation in coelomocytes of Caenorhabditis elegans. Such controllable emergent behavior of host-cargo complexes has been used as powerful probes to interrogate biological phenomena both in living cells and whole organisms. 4.5. DNA cages in materials science DNA nanostructures have been combined with porous materials for creating composite materials. For example, conductive nanoporous antimony-doped tin oxide has been used to host tetrahedral DNA nanostructures with high affinity.91 DNA nanocages were incorporated into the conductive metal oxide by tuning the pore size (Figure 8A). The defined edges of the tetrahedron provide desired spatial arrangement of guest molecules, even within the pores of the metal oxide. Such composite materials hold promise in applications such as photovoltaics, sensors, and solar fuel cells. A DNA tetrahedron has also been hosted in metal organic frameworks (MOFs) to form DNA/MOF composite materials.92 DNA tetrahedron in the MOF was found to be more stable in deionized water at room temperature compared to the DNA nanostructure by itself.


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Hollow nanostructures constructed using DNA origami have been used as molds to cast inorganic materials (Figure 8B).93 The mold contained an Au 'seed' (for example, a 5 nm AuNP) that grows into the specified Au or Ag moldshaped material under suitable chemical conditions. This strategy was used to mold a variety of shapes such as cuboids, triangles and spheres. Moreover, the DNA mold provides spatial addressability on the surface thereby allowing the construction of higher order composite materials. A similar technique using DNA origami shells has been used to mold 40 nm long rod-like AuNPs with a quadratic cross section.94

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such as additional DNA strands, pH and temperature. Incorporation of such dynamic features in DNA cages allows for not only the encapsulation of guest molecules such as proteins, peptides or nanoparticles, but also the release of these guests as and when required. This functionality of DNA cages is especially useful for theranostic applications where these structures can be designed to operate based on the environment to which they are delivered to. It is imperative to further analyze the mechanism by which these structures enter cells, the bioavailability of the encapsulated drug and the biocompatibility of these structures.95 Targeted localization of such nanostructures in cells can be monitored by modifying the component DNA strands to contain fluorophores or target-specific antibody fragments. In addition, further research is required to produce such DNA cages in high throughput, making them available for large scale production of drug-containing delivery vehicles. For example, methods have been reported for scaling up the production of structures based on DNA origami.96 Nanostructures made using DNA origami are useful for applications in biotechnology, especially in drug delivery.97-98 More compact DNA capsules constructed using the concept of DNA bricks are also viable for this purpose.99 DNA-based structures offer many advantages for applications in targeted delivery: they are efficiently internalized into mammalian cells,87-88 exhibit enhanced resistance to enzymatic digestion100 compared to linear dsDNA and can be obtained with high purification yields.101 Another aspect of such designed structures is that they provide site-specific attachment and encapsulation of functional molecules such as enzymes. For example, cages built using DNA origami have been used to enhance the catalytic activity of enzymes.102 In addition, the emergence of RNA nanotechnology103 has spurred the use of RNA in creating cage-like structures.104

Figure 8. DNA cages for materials science applications. (A) Size-selective incorporation of tetrahedral DNA nanocages into antimony-doped tin oxide. Reproduced with permission.91 Copyright 2011 ACS. (B) Assembly of the mold and casting growth of a metal particle within a DNA nanostructure. Reproduced with permission.93 Copyright 2014 AAAS.

5. CONCLUSION The design and construction of DNA nanostructures has advanced from small motifs and objects to large arrays and complex wireframe structures. Diverse strategies have been developed to construct a variety of DNA cages, a collection of which were discussed in this review. The advantage of such DNA cages is that they are flexible in design, allowing reconfiguration triggered by external stimuli

The cost of DNA strands has been reduced to less than $0.001/bp in recent times due to the development of onchip synthesis, with a yield of ~1 µg.105 Strategies aimed towards large-scale synthesis of DNA strands with considerably higher yields will further reduce production costs. Moreover, in vivo cloning techniques for amplifying DNA nanostructures may substantially reduce the fabrication costs of DNA cages.106 In addition, custom-tailored DNA and RNA origami scaffolds expand the size range of constructs that can be assembled (instead of a fixed 7249-nt scaffold length M13).107 The interactions between the subunits making up the DNA nanostructures can be strengthened using a variety of strategies such as triplex formation,108-109 site specific cross-linking110-111 and click reactions.112-113 Current facilities in molecular simulations allow the characterization of such designed structures in silico114 and can also be used to analyze the behavior of such complexes.115 In addition, the components for building such architectures can be expanded to the use of unnatural base pairs116 and xeno nucleic acids.117 The unrestricted design prospects provided by DNA and the superior features of DNA-based cages make them promising candidates for the development of a wide variety of functional materials.


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AUTHOR INFORMATION Corresponding Author *A. R. Chandrasekaran. Email: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank June Won for recreating images in some of the Figures. We thank Dr. Ken Halvorsen (SUNY Albany) and Dr. Dhiraj Bhatia (Institut Curie) for discussions and helpful comments on the article.

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(117) Taylor, A. I.; Beuron, F.; Peak-Chew, S. Y.; Morris, E. P.; Herdewijn P.; Holliger, P. Nanostructures from Synthetic Genetic Polymers. ChemBioChem 2016, 17, 1107-1110.


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DNA Nanocages - Chemistry of Materials (ACS Publications)

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