Precise organization of metal nanoparticles on DNA origami template

Methods 67 (2014) 205–214

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Methods journal homepage: www.elsevier.com/locate/ymeth

Precise organization of metal nanoparticles on DNA origami template Qing Liu, Chen Song, Zhen-Gang Wang, Na Li, Baoquan Ding ⇑ National Center for Nanoscience and Technology, No. 11 BeiYiTiao ZhongGuanCun, Beijing 100190, China

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Article history: Available online 21 October 2013 Keywords: DNA origami Self-assembly Metal nanoparticle Plasmonic

a b s t r a c t Nanoscale assemblies of metal nanoparticles in one dimension (1D) to three dimensions (3D) can exhibit novel phenomena that are not observed in the amorphous state. Bottom-up assembly technique is expected to overcome the resolution limit of top-down method and casts a new light on the nanofabrication field. DNA origami, which is mainly used to construct discrete and addressable nanostructures, can be utilized to assemble functional colloidal nanoparticles into delicate geometries with interesting properties. This review aims to summarize the methods that use DNA origami structures as templates to precisely organize metal nanoparticles, such as gold nanospheres (AuNSs) gold nanorods (AuNRs) and silver nanoparticles (AgNPs). The potential applications and the perspective are also discussed. Ó 2013 Elsevier Inc. All rights reserved.

1. Introduction As metal nanoparticles possess many intriguing optical and electrical properties that are not observed in bulk materials [1–4], they are arousing increasing interest in the field of nanoscience and nanotechnology. The electron density of metal nanoparticles can couple with electromagnetic radiation of incident light and the plasmons at the surface of metal are confined to the finite volumes, which enable the manipulation of light–matter interactions and provide the opportunity to overcome the diffraction limit. Such plasmon oscillations are also termed as localized surface plasmon resonances (LSPR). Moreover, the plasmonic nanoparticles exhibit various absorption, scattering and coupling properties that are dependent on shapes, sizes and distance between particles. These properties have been widely used for sensing [5–7], medicine diagnosis [8–11], cellular imaging [12,13] and constructing nanoelectronic and nanophotonic devices [14–19]. The photothermal property of the plasmonic nanoparticles can also be applied for cancer therapy [20,21]. The optical properties of plasmonic nanoparticles are strongly affected by their morphologies, chemical composition and dielectric environment. Great theoretical development has been made, including classical electrodynamic and quantum theories, to describe the plasmonic properties of individual metal nanoparticles and their assemblies [22,23]. Computational modeling tools are also available for simulating the plasmon coupling effects of nanoparticle complex [24–26]. The simulation results provide fundamentals for engineering the assemblies of metal nanoparticles experimentally to achieve customized optical properties, in which each plasmonic element is arranged precisely and rationally. ⇑ Corresponding author. E-mail address: [email protected] (B. Ding). 1046-2023/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ymeth.2013.10.006

Plasmonic coupling arises significantly only when the centerto-center distance of the particles is less than 1.5 times the particle diameter and it is confined to a small region between the neighboring particles [27]. Towards this goal, two strategies are usually adopted: top-down fabrication and bottom-up self-assembly. Traditional top-down fabrication approaches, such as photolithography and electron beam lithography [28–33], are challenged by their resolution limit and deficient capability of fabricating exquisite 3D architectures. In comparison, bottom-up self-assembly is expected to overcome these limitations and cast a new light on the nanoscience and technology [34–39]. Deoxyribonucleic acid (DNA) is an ideal building block for the construction of sophisticated nanostructures, because of the excellent features such as sequence programmability, specific molecular recognition, the rigidity of the double helix, sequence-independent nanoscale structure, commercial automatic synthesis, versatile chemical modifications and the ability of enzymatic scission and ligation, etc. These properties make DNA one of the promising molecules to organize functional nano-objects, such as metal nanoparticles. Many plasmonic assemblies have been constructed through hybridization of the DNA ligands that were functionalized on the surface of metal nanoparticles, including dimer [40], trimer [41], chiral pyramid [42,43], satellite-like nanoparticle assemblies [44,45] and 3D assemblies [46]. However, there are only very limited kinds of nanoparticle assemblies that could be constructed through direct hybridization between nanoparticle–DNA conjugates. Rigid DNA scaffolds provide great potential to fabricate well-defined metal nanoparticle assemblies. Metal nanoparticles can be positioned on tile-based DNA nanostructures, such as doublecrossover and 4  4 tile based 2D lattice. With careful design of the position of the capture strands on DNA-tile nanostructures, complex nanoparticle assemblies were constructed, such as gold

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Fig. 1. (a) Schematic illustration of the basic principle of DNA origami technique. Adapted with permission from Ref. [57]. Copyright 2010. Macmillan Publishers Ltd. (b) AFM micrographs of the assembled smiley structures. The scale bar is 100 nm. Adapted with permission from Ref. [58]. Copyright 2006. Macmillan Publishers Ltd.

nanoparticles 2D array [47,48]. Through substitution of DNA strands in the array with single-DNA-conjugated metal nanoparticles, aligned metal nanoparticle chains [49], metal nanoparticle 2D array [50] as well as spiral chains and double helices [51] can be produced. However, the metal nanoparticles assembled on DNAtile templates typically included several assemblies that differed in nanoparticle number. It is challenging to obtain assemblies with identical number of nanoparticles. It is difficult to use traditional DNA-tile assembly to produce DNA array with uniform and finite size. Recently, rationally designed DNA tiles can be used to construct 2D or 3D finite size nanostructures which may be utilized for delicate particles assemblies [52–56]. DNA origami technique, which was first demonstrated by Paul W.K. Rothemund in 2006 [57,58], is mainly used to construct discrete and well-arranged nanostructures (Fig. 1). This assembly technique is to fold a long viral single-stranded DNA (scaffold strand) with the help of hundreds of appropriately designed short single strands (staple strands). Almost any arbitrary 2D [58–60] and 3D [61–67] DNA nanostructures with well-defined sizes, shapes, and fully spatial addressability can be constructed through DNA origami technique. Instead of purified DNA strands which are usually required for traditional tile assembly, crude staple strands can be directly used for annealing without purification. Thus, much time and effort can be saved. For regular DNA origami structures, the yield can reach above 80% with just several hours annealing. Because all staple strands are unique in both sequence and position, they can be spatially distinguished at a resolution of 6 nm. Nanoscale materials such as metal nanoparticles [14,68–70] or semiconducting nanocrystals [71–74] functionalized with complementary sequences can be anchored via hybridization with the protruded capture strands. A more direct approach to arrange nanoparticles on DNA origami is to replace one of the staple strands with the DNA modified nanoparticles and to position the nanoparticles during the folding of the scaffold [75]. In this review we aim to describe the use of DNA origami as a template to precisely organize metal nanoparticles, including AuNSs, AuNRs and AgNPs. The detailed protocols will be highlighted.

2. Functionalize metal nanoparticles with DNA Thiolated oligonucleotide strands can be conjugated to the surface of specific metal nanoparticles, serve as negatively charged ligands to keep the nanoparticles from aggregation, and provide sequence-specific recognition for nanoparticles assembly. The

functionalization reaction can be influenced by several factors. First of all, for the metal nanoparticles with larger size, increased amount of DNA or stabilizer molecules was necessary for stabilization of DNA–metal nanoparticle conjugates in the saline [76]. With regard to the DNA sequence, it is reported that adenine had the strongest affinity to the surface of gold nanoparticles, while the affinity of thymine to gold surface was weakest among the four nucleotides [77]. Due to the weaker interaction of the thymine with the gold surface, higher coverage of thiolated poly(thymine) oligonucleotides on the surface of gold nanoparticles could be attained [78]. Based on the stronger affinity of adenine to gold surface, it was also demonstrated that poly(adenine) can serve as an effective anchoring block for preferential binding with the gold nanoparticles surface, instead of the thiolated oligonucleotide strands [79]. The buffer conditions, particularly the salt concentration and the pH value, play an important role in the functionalization. On one hand, higher salt concentration could increase the oligonucleotide loading, because salt reduced the charge repulsion between DNA and the capping ligand (citrate or BSPP) on gold nanoparticles [76]. The salt concentration of the buffer should be increased progressively within tens of hours, because the high concentration of salt could also result in the aggregation of metal nanoparticles. On the other hand, the buffer with low pH value could tremendously accelerate the conjugation reaction between the thiolated DNA and gold nanoparticles [44,80]. In the citrate buffer at pH 3.0, adenine and cytosine were both positively charged, which could reduce the charge repulsion between negatively-charged AuNPs and DNA molecules and allow fast adsorption. The reaction between thiolated oligonucleotide strands and gold nanospheres only required a few minutes, compared to the salt-aging method that took more than 40 h. Not only the gold nanospheres, but the gold nanorods could be functionalized with DNA molecules through this low pH-assisted method [44]. Besides the factors mentioned above, the functionalization is also influenced by reaction temperature: too high temperature (>70 °C) will reduce the stability of metal nanoparticles to be modified, and desorb the thiolated DNA from the gold nanoparticle surface [81]. Both monovalent and polyvalent surface functionalizations with DNA have been employed for assembling metal nanoparticles. When thiolated DNA strand is incubated with metal nanoparticles (e.g., Au, Ag or Pt) with 1:1 molar ratio in buffer solution, the modified products are usually a mixture containing single-, double- and multiple-strands-attached nanoparticles. Single-strand-modified metal nanoparticles can be obtained through purification with gel electrophoresis [82] or anion-exchange high

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performance liquid chromatography (HPLC) [83]. The gel electrophoresis method is usually limited to metal nanoparticles with small size (615 nm) because it is difficult to discriminate the single- or double-DNA-modified (670 bases) nanoparticles of larger size in the gel electrophoresis. A modified gel electrophoresisbased approach was developed to produce 15-nm monofunctionalized metal nanoparticles with shorter DNA length (40 bases), in which an extended DNA strand was used to hybridize with the thiolated DNA anchored on the surface of nanoparticles [84,85]. Because of the increased molecular weight of the extended strand, charge repulsion and the steric force, the yield for single short DNA functionalized metal nanoparticles was dramatically enhanced. Based on this extended-strand strategy, multiple-extended-strands method was come up with in which one extended strand were further lengthened by adding subsequent extended strands [86,87]. Through hybridizing successively with five 100 bases extended strands, gold nanoparticles as large as 36 nm in diameter conjugated to a single DNA single strand as short as 30 bases were obtained through electrophoretic purification. Using the HPLC method, discrete DNA–metal nanoparticle conjugates in which DNA lengths reached as short as 15 bases for 20-nm metal nanoparticles could be obtained [83]. However, the high cost and preparatory procedure of HPLC limit the application. Several methods were used to adjust the reaction conditions [88], whereas the yield of single-DNA modified metal nanoparticle was not high. A magnetic-microparticle-based strategy was developed, in which monofunctionalized metal nanoparticles with the diameter up to 30 nm was fabricated [89]. In this method, both a target-capture sequence and a protecting sequence were used with very low molar ratios. As a result, only one target-capture strand was attached to each nanoparticle and the nanoparticles were stabilized with a large amount of protecting strands. Subsequently, the modified nanoparticles with single target-capture strand were captured by magnetic particles functionalized with complementary sequence and purified by a magnetic-separation process. Through this method, monofunctionalized metal nanoparticles were obtained with a high yield. In addition, polyvalent functionalization was developed to prepare metal nanoparticles fully covered by thiolated DNA strands, which in principle can be used for metal nanoparticles in any diameter. Most recently, a universal route by which almost any kind of inorganic nanoparticles could be functionalized with DNA has been reported [90]. As long as the nanoparticles were stabilized by hydrophobic capping ligands that were very common for nanoparticles synthesized in organic media, the azide-bearing amphiphilic polymer was liable to coat the nanoparticles through hydrophobic interaction. Thereafter, dibenzocyclooctyl (DBCO) modified DNA molecules could be easily coupled to the surface of the azide-bearing polymer-coated nanoparticles through strain-promoted azide-alkyne cycloaddition. Four kinds of nanoparticles (oleylamine-protected CdSe/ZnS core–shell quantum dots, oleic-acid-protected iron oxide nanoparticles, oleylamineprotected platinum nanoparticles and dodecanethiol-functionalized gold nanoparticles) were chosen to be functionalized with DNA molecules, which demonstrated the universality of this strategy.

3. Fabricate metal nanoparticle assemblies with DNA origami 3.1. Arrangement of AuNSs on DNA origami Gold nanoparticle is a common colloid material possessing great potential in various applications and it can be readily modified by DNA molecules through thiol-Au bonding. Therefore, the

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arrangement of AuNP via DNA self-assembly has been widely explored. Initially, monofunctionalized AuNSs were used for the positioning of DNA–AuNP conjugates [47,84,91]. However, such assembly usually suffers from low yield because the monovalent thiol-Au linkage between DNA and AuNSs is not very stable. Moreover, the DNA–AuNP conjugates tend to aggregate in buffer solution containing cations which are required for DNA self-assembly. Sharma et al. [75] proposed a strategy that 10-nm AuNP and lipoic acidmodified DNA oligonucleotide were first mixed in equimolar ratio to prepare mono-DNA-modified AuNP through stronger divalent thiolate-Au linkage. The stable conjugate was then used instead of a staple strand to fold the scaffold into rectangular DNA origami structure with the help of other DNA staple strands (Fig. 2). To ensure the dispersibility of the nanoparticles in high Mg2+ concentrations required for DNA self-assembly, the surface of the nanoparticles was passivated using a layer of short oligonucleotides. The short oligonucleotides were composed of five thymine residues that were modified with monothiolated group at the end. After slow annealing, fixed-size DNA origami nanostructures carrying a discrete number of AuNSs at desired positions were obtained. Atomic force microscopy (AFM) measurement revealed that the yield of the nanoparticles on DNA origami reached 91%, almost twice as high as the yield of the origami-AuNP assembly obtained using a monovalent nanoparticle–DNA conjugate. Besides divalent thiolated DNA molecules, trithiol- [92] and tetrathiol-capped [93] oligonucleotides were reported and the corresponding DNA–AuNP conjugates exhibited higher stability and assembly efficiency than those prepared from monothiol and cyclic dithiol-capped oligonucleotides. It is expected to use trithiol- or tetrathiol-capped DNA molecules as linkage to assemble metal nanoparticles on the origami template. Monofunctionalization of metal nanoparticles suffered from the cumbersome purification procedures and limited particles size. It is more advantageous in the fabrication of small-sized self assemblies, such as tetramers, trimers or dimers, compared with multifunctionalization of nanoparticles. The metal nanoparticles fully covered by DNA molecules facilitate more stable and diverse assembly of nanoparticles to the origami via anchoring the nanoparticles at predetermined positions through DNA hybridization. Ding et al. [14] used six fully DNA-covered AuNSs to construct a linear chain of different-sized AuNSs with well-controlled orientation and spacing less than 10 nm (Fig. 3a). In this assembly design, specific staple strands of the DNA origami structure extended to form six groups of sticky-ends with different sequences, which were all displayed on the same side of the origami template surface. Three identical-sequence sticky-ends were designed to fasten one AuNP at predesigned location and 18 sticky-ends were used to organize the six AuNSs. AuNSs with 5 nm, 10 nm and 15 nm diameters were fully modified with thiolated-DNA strands that were complementary to the corresponding sticky ends. The purified origami structure and DNA–Au nanosphere conjugates were mixed with a molar ratio of 1:1 and annealed to facilitate the complementary strands hybridization. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) micrographs demonstrated the formation of the linear six-AuNSs chain. A plasmonic absorption band shift was observed with spectrometer before and after annealing, which agreed with the theoretical study and indicated the interparticle plasmonic interaction [94]. Most recently, with this method, AuNSs with size up to 20 nm have been precisely organized on DNA origami template [95]. By employing the spatial addressability on both sides of the rectangular DNA origami, four identical 20-nm AuNSs were assembled into stereoisomeric 3D nanostructures. Concretely, three AuNSs were anchored on one side of the DNA template and the fourth AuNP was positioned on the opposite side, directly below one of the three AuNSs.

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Fig. 2. Schematic illustration of the preparation of AuNP–DNA conjugates with a divalent thiolate-Au linkage and their employment in the self-assembly of DNA origami. Reproduced with permission from Ref. [75]. Copyright 2008. American Chemical Society.

Fig. 3. (a) Schematic illustration of the self-assembly process of six-AuNP linear structures and representative SEM and TEM micrographs. The scale bars in the SEM and TEM micrographs are respectively 200 nm and 50 nm. Adapted with permission from Ref. [14]. Copyright 2010. American Chemical Society. (b) SEM micrographs of different fused metallic nanostructures. All scale bars are 500 nm. Reproduced with permission from Ref. [96]. Copyright 2011. American Chemical Society.

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Through altering position of the fourth AuNP, left- and righthanded structures were obtained. TEM micrographs taken at different tilting angles verified the preconceived 3D geometrical structures of the four AuNSs and the measured circular dichroism (CD) signals were in accordance to the theoretical model. Using the similar strategy, Pilo-Pais et al. [96] succeeded in positioning several 5 nm AuNSs onto rectangular DNA origami at specific locations. Then through electroless deposition of silver, the metal nanoparticles were fused together and predesigned metallic nanostructures such as rings, pairs of parallel bars, and H shapes were created (Fig. 3b). This research successfully demonstrated a new strategy to fabricate complex components for nanoelectronic and nanophotonic applications. Bottom-up self-assembly technique offers high spatial resolution and precision for the arrangement of various components in microscopic dimensions, while top-down fabrication such as lithographic patterning affords visual control at the macroscopic and mesoscopic scale. Combining the two techniques enables both large-area addressability and orientation control of the plasmonic assemblies. Noteworthily, the size of DNA origami structures is usually about 100 nm, approximating the size that can be routinely manipulated by lithography technology. This means DNA origami technique may bridge the microcosm to the macrocosm. It is believed that integration of the top-down fabrication and bottomup self-assembly will advance the nanodevice fabrication significantly. Kershner et al. [97] reported the DNA origami-shaped binding sites could be created on technologically useful materials such as SiO2 and diamond-like carbon through electron beam lithography and dry oxidative etching. After that, the DNA origami structures in buffer with 100 mM Mg2+ adsorbed efficiently to the binding sites with high selectivity. This technique offers a possible approach to place individual molecule or a defined number of molecules (or nanoparticles) that were assembled to DNA origami in a pattern on a solid surface. Subsequently, Hung et al. [98] assembled 5-nm AuNSs with DNA origami structure and then deposited the DNA origami–AuNSs conjugates onto the lithographically patterned substrates. AFM images confirmed the AuNSs were successfully assembled into large-area, spatially ordered, 2D arrays. Based on 2D origami structures, 3D helical architectures of metal nanoparticles can also be created. Shen et al. [99] presented a strategy to obtain 3D plasmonic helix architecture of AuNSs via transformation of 2D rectangular DNA origami sheet (Fig. 4). First, rectangular DNA origami structure was designed with fifteen binding sites. The binding sites were distributed along two linear chains

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on one side of the origami template with well-controlled spacing. Simultaneously, the sequences of the two long sides of the rectangular origami template were modified to be complementary to those of the folding DNA strands (panel I). Then, 10 nm or 13 nm AuNSs fully covered with thiolated DNA strands were attached to the binding sites and displayed 2D parallel configuration (panel II). Upon the addition of the folding strands, the rectangular origami sheets were rolled up, resulting in the formation of hollow DNA origami tube with 3D helical geometry of the AuNSs (panel III). TEM micrographs (Fig. 4b) and the significant circular dichroism signals (Fig. 4c) around the plasmonic resonance of the AuNSs demonstrated the formation of plasmonic chiral structures. In addition to 2D DNA origami sheet, 3D DNA origami architectures were also utilized to organize metal nanoparticles. Kuzyk et al. [100] designed a 24-helix DNA origami bundle for the highyield production of left- and right-handed nanohelices consisting of nine AuNSs. The helical structures obtained exhibited defined CD signals and optical rotatory dispersion effects at visible region, which were in agreement with the theoretical predictions [101]. Furthermore, electroless deposition was used to grow a thin layer of Ag shell on the assembled AuNSs. Strong coupling effect and regulated CD in the blue spectral region corresponding to surface plasmon frequency of Ag were achieved because the Ag coating generated enlarged particles and reduced spacing between particles. Zhao et al. [102] succeeded in encapsulating AuNSs into a 3D honeycomb-pleated DNA origami nanocage with an outer dimension of 41 nm  30 nm  21 nm and an inner dimension of 10 nm  10 nm  21 nm (Fig. 5). Both of the 5 nm and 10 nm AuNSs covered with 15-nucleotides single strand DNA (ssDNA) were readily accommodated into the inner cavity bearing three or four capture strands, with the yield higher than 90%. When the size of the AuNSs reached up to 15 nm that was larger than the theoretical size of the inner cavity, the encapsulation efficiency was about 68%. The successful encapsulation of 15-nm AuNP into the cavity indicated the inherent flexibility of the DNA origami structures. Besides the inner cavity of the DNA origami nanocage, the outer surface designed with capture strands could also be utilized to assemble AuNSs. TEM micrographs demonstrated one to four AuNSs were well organized by virtue of the inner and outer surfaces of the nanocage. Recently, Acuna et al. [103] reported a DNA-directed selfassembled nanoantenna that was made up of a DNA origami pillar with one or two AuNSs (Fig. 6). The DNA origami was composed of a pole of 12-helix bundles and a base formed by three 6-helix

Fig. 4. 3D Helical AuNPs array constructed via 2D rectangular DNA origami. (a) Schematic representations of the system. (b) TEM micrographs of the 3D AuNPs helices after rolling up. All scale bars are 10 nm. (c) Circular dichroism signals of the plasmonic chiral helical structures. Adapted with permission from Ref. [99]. Copyright 2012. American Chemical Society.

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Fig. 5. Schematic diagrams and corresponding TEM micrographs of the 3D DNA origami nanocages containing various numbers of 5 nm AuNPs. Reproduced with permission from Ref. [102]. Copyright 2011. Wiley-VCH Verlag GmbH & Co. KGaA.

Fig. 6. Schematic illustration of the DNA-directed self-assembled nanoantenna. Reproduced with permission from Ref. [103]. Copyright 2012. AAAS.

bundles. The whole length of the DNA origami pillar was 220 nm. The pole bore a docking site for single fluorescent dye and the base was immobilized on the cover slip through biotin–neutravidin interaction. The nanoantenna was fabricated by attaching one or two DNA-functionalized AuNSs to the DNA origami pillar through 15-base capturing strands. Attached AuNSs served as nanoantenna and could focalize incident light in the hotspot between the nanoparticles. A fluorescent dye was positioned at the docking site and acted as an emitter. The dependence of the fluorescence intensity on the size and number of AuNSs was investigated and a maximum

of 117-fold fluorescence enhancement was observed when the dye molecule was positioned in the 23-nm gap between two 100-nm AuNSs. Undoubtedly, this research paved a way for nanoscale light control and single-molecule imaging. 3.2. Arrangement of AuNRs on DNA origami As a type of anisotropic nanomaterials, gold nanorods (AuNRs) possess unique optoelectronic properties compared with AuNSs. For example, AuNRs have a high optical extinction cross section

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in the range of visible and near-infrared (NIR) wavelengths and strong localized plasmonic fields at their tips [104]. Hence, signals disparate to that of the AuNRs arrays may arise via the accurate arrangement of AuNRs. In contrast to top-down electron beam lithography-based fabrication of AuNRs arrays [105], Pal et al. [106] established a bottom-up self-assembly method to construct well-organized AuNR dimers with controlled inter-rod angles and distances using triangular DNA origami template (Fig. 7). The general assembly procedure was similar to that of AuNSs, including modifying AuNRs with multiple thiolated DNA strands, designing DNA origami template with five complementary capture strands to bind one AuNR, mixing the purified DNA–AuNR conjugates and DNA origami template and slow annealing. Because it was more difficult to precisely assembled AuNRs on DNA origami template, many cycles of annealing were indispensable for high-yield assembly. The formation of four kinds of discrete assembly structures of AuNRs with different relative orientation was verified by TEM micrographs, and the two well-ordered AuNRs can interact with each other in an orientation-dependent manner. The strategy used in work proved the feasibility of arranging anisotropic metal nanostructures in highly ordered fashions using DNA origami template and promoted the study of nanoscale plasmon interactions.

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of the oligonucleotide, a sulfur atom replaced a non-bridging oxygen of the phosphate backbone. The multiple sulfur atoms in the ps domain of the DNA backbone enabled high affinity of the ps-po-DNA to the surface of the AgNPs. At the 30 -end of the ps-po-DNA, a number of bases were modified with the normal phosphate diester (po) backbone for the further hybridization. After functionalization, the DNA–AgNP conjugates were hybridized with 5-nm monofunctionalized AuNSs, resulting in the bimetallic core-satellite nanoclusters. Using the same strategy, Pal et al. [69] obtained DNA-covered 20-nm AgNPs and incorporated DNA–AgNP conjugates on the triangular DNA origami template in different groupings. The assembly procedure was analogous to that for assembling AuNSs on DNA origami template. After the assembly, discrete and well-ordered silver nanoarchitectures with precisely tunable center-to-center distance were constructed with high yield (Fig. 8). This research overcame the fundamental limitation to the precise assembly of AgNPs-based nanostructures and provided potential for better insight into metal nanoparticles interactions. 4. Practical protocols 4.1. Preparation of DNA origami template

3.3. Arrangement of AgNPs on DNA origami AgNPs have gained much interest recently because of their excellent catalytic properties [107] and roles in enhancing Raman scattering [108]. However, the arrangement of AgNPs via DNA self-assembly has been rarely reported. This is due to the instability of AgNPs and the difficulty in modification with mono-thiolated DNA strands. AgNPs are apt to be oxidized and usually suffered from irreversible aggregation when subjected to high salt concentration, whereas the dispersion stability is crucial for efficient selfassembly of AgNPs with DNA nanostructures. There have been many attempts to overcome the obstacles. Lee et al. [109] have demonstrated that due to the strong affinity of multiple cyclic disulfides for the AgNP surface, increasing the number of cyclic disulfide-anchoring groups in the capping ligands could enhance the stability of AgNPs under high salt concentrations. In the light of this research, Pal et al. [110] succeeded in functionalizing 32nm AgNPs with chimeric phosphorothioate modified DNA (ps-poDNA). The ps-po-DNA consisted of two parts. At its 50 -end, a number of bases were linked to the phosphorothioate backbone for stabilizing the AgNPs. In the consecutive phosphorothioate backbone

For the 2D DNA origami template [14,99,111]: Long viral ssDNA (M13 strand, 5 nm) was mixed with the short unmodified staple strands (25 nm) and modified staple strands (capture strands, 5 nm). The assembly was conducted in 1 TAE-Mg2+ buffer (Tris, 40 mM; Acetic acid, 20 mM; EDTA, 2 mM; Magnesium acetate, 12.5 mM; pH 8.0) by slowly cooling from 65 °C to 45 °C at the rate of 2 °C per 10 min and then cooling from 45 °C to room temperature over 30 min. Before used, the solution of origami needed to be purified through Amicon Ultra centrifugal filters (Ultracel100 K, Merck Millipore, 1900 rcf, 4 min) to remove excessive staple strands. For the 3D DNA origami template [102,111]: After mixing the M13 strand with unmodified and modified staple strands, the assembly was conducted by slowly cooling from 65 °C to 45 °C at the rate of 2 °C per 40 min and then cooling from 45 °C to room temperature over 30 min in a pH 8.0 buffer containing 5 mM Tris, 1 mM EDTA and 16 mM MgCl2. Before used, the solution of origami needed to be purified through Amicon Ultra centrifugal filters (Ultracel-100 K, Merck Millipore, 1900 rcf, 4 min) to remove excess staple strands.

Fig. 7. Schematic diagrams and corresponding TEM micrographs of four kinds of discrete AuNRs architectures assembled by DNA origami. All scale bars are 100 nm. Reproduced with permission from Ref. [106]. Copyright 2011. American Chemical Society.

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Fig. 8. Schematic diagrams and corresponding TEM micrographs of four kinds of discrete AgNPs architectures assembled by DNA origami. The scale bar is 100 nm. Reproduced with permission from Ref. [69]. Copyright 2010. Wiley-VCH Verlag GmbH & Co. KGaA.

4.2. Modification of metal nanoparticles Gold nanospheres: The AuNSs purchased (Ted Pella, Inc) were usually covered by weak ligands such as citrate ions or tannate ions, which could not withstand the high salt concentrations required for functionalization. Therefore, first of all, it was necessary to stabilize the AuNSs through ligand exchange. The procedure is listed as follows [14]. Bis(p-sulfonatophenyl) phenylphosphine dihydrate dipotassium salt (BSPP) (15 mg) was added to the solution of AuNSs (2.32 nm, 50 mL) and the mixture was shaken overnight at room temperature. NaCl was added slowly to this mixture while stirring until the color changed from deep burgundy to light purple. The resulting mixture was centrifuged at 845 rcf for 30 min and the supernatant was carefully removed with a pipette. AuNSs were then resuspended in 1 mL solution of BSPP (2.5 mM). Upon mixing with 1 mL methanol, the mixture was centrifuged. After removing the supernatant, the AuNSs were resuspended into 1 mL BSPP solution (2.5 mM) followed by estimating the concentration of the solution from the UV–vis absorbance at 520 nm. On the other hand, thiolated oligonucleotides were treated with tris(2-carboxyethyl) phosphine (TCEP) aqueous solution (20 mM, 1 h) to reduce the disulfide bond to monothiol and purified using size exclusion columns (G-25, GE Healthcare) to get rid of the small molecules. Then monothiolated oligonucleotides and phosphinated AuNSs were incubated at a DNA to AuNP molar ratio of more than 200:1 in 0.5 TBE buffer (1 TBE buffer: 89 mM Tris, 89 mM boric acid, 2 mM EDTA, pH 8.0) containing 50 mM NaCl for 20 h at room temperature. Later, the concentration of the NaCl was slowly increased to 300 mM for another 20 h in order to increase the binding efficiency of thiolated DNA onto the surface of AuNSs. Prior to use, the DNA–AuNS conjugates were washed with 0.5 TBE buffer containing 300 mM NaCl using Amicon Ultra centrifugal filters (Ultracel-100 K, Merck Millipore, 1900 rcf, 4 min) to get rid of the extra oligonucleotides. The concentration of these DNA–AuNP conjugates was estimated from the optical absorbance at 520 nm. Silver nanoparticles [69,110]: AgNPs (0.12 nm, 1 mL) purchased from Ted Pella, Inc was concentrated 10 times by centrifugation

(6010 rcf, 40 min) and re-dispersed in 1 TBE buffer (100 lL). Then chimeric phosphorothioate modified DNA was add to the AgNPs solution with a final concentration of 8 lM and kept shaking overnight on a shaker. After that, 4 M NaCl was added by small aliquots (1 lL each) over 24 h to raise the final NaCl concentration to 350 mM and the solution was incubated overnight again in order to increase the binding efficiency of chimeric phosphorothioate modified DNA onto the surface of AgNPs. Before used, the excessive modified oligonucleotides was removed through centrifugation (6010 rcf, 40 min) and re-dispersed to a buffer solution that contained 1 TBE and 350 mM NaCl. This centrifugation and re-dispersion procedure was repeated three times and the concentration of AgNPs was determined by measuring the absorbance at 400 nm. Gold nanorods [106]: AuNRs with various dimensions and aspect ratios were usually synthesized through the seed-mediated growth method [112–114]. Take the AuNRs mentioned above for example, the synthesis of them was carried out as follows [115]. First, 60 lL of 10 mM ice cold NaBH4 solution was added to 1 mL of 2.5 mM HAuCl4 solution containing 100 mM CTAB and then vortexed vigorously. The color of the solution immediately changed to yellowish brown, indicating the formation of AuNP seeds which would act as nucleation points for later-on growth. After the AuNP seeds were formed, 250 lL of 1 mM AgNO3 solution was added to 1 mL of 10 mM HAuCl4 solution containing 100 mM CTAB. After gentle mixing, 70 lL of 79 mM ascorbic acid solution was added and mixed thoroughly. Then, to this mixture 12 lL of the previously prepared AuNP seed solution was added and kept undisturbed for several hours until the color of the solution turned purple, which indicated the formation of AuNRs. After that, 500 lL AuNRs solution was centrifuged (15 min, 4600 rcf) and the pellet was resuspended into 500 lL of nanopure water while discarded the supernatant. Then, the solution was centrifuged again and the collected pellet was resuspended into 10 mM CTAB solution. For enhancing the affinity of thiolated DNA to the AuNR surface, a thin layer of Au on the AuNRs surface needed to be created by adding ascorbic acid (1 mM) and HAuCl4 (0.005 mM) to 0.9 nm solution of AuNRs containing 10 mM CTAB. Finally, the

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AuNRs solution was washed twice by centrifugation and resuspension in nanopure water and the concentration was measured via UV–Vis spectroscopy. On the other hand, to reduce the S–S bond in thiolated DNA to monothiol, 40 lL of 200 mM TCEP aqueous solution was added to 40 lL of 1 mM DNA solution and then incubated overnight. After removing the non-DNA molecules using a G25 spin column, the mixture was added to 300 lL of AuNR solution containing 0.01% sodium dodecyl sulfate (SDS) and incubated overnight. Then 10 TBE buffer was added to bring the final buffer concentration to 1 TBE. After several hours, a 5 M NaCl solution was slowly added to bring the final concentration of NaCl to 500 mM during 24 h and then the mixture was kept undisturbed at room temperature overnight. Before used, the excessive DNA was removed by repeated centrifugation (3380 rcf, 15 min) and re-suspension to 1 TBE buffer three times. The concentration of AuNRs was measured using UV–Vis spectroscopy.

213

DNA origami is so far a highly promising approach to organize nanoparticles in nanometer accuracy. Although the field of DNA directed construction of functional assemblies is in its early stage, the versatility and the ability of DNA origami as designer templates provide great potential in the development of novel and miniaturized optical and electronic devices. With the unique DNA origami system, wide applications in sensing, waveguiding, energy harvesting or medical diagnostics may be generated. Acknowledgements The authors are grateful for the financial support from National Science Foundation China (21222311, 21173059, 91127021 and 21205022). National Basic Research Program of China (973 Program, 2012CB934000), 100-Talent Program of Chinese Academy of Sciences (B.Q.D), Beijing Natural Science Foundation (2122057). References

4.3. Organization of metal nanoparticles on DNA origami template Gold nanoparticles [14]: Purified DNA origami and DNA–AuNP conjugates were mixed together with 1:1 ratio of binding site to AuNP and annealed from 43 °C to 23 °C for 24 h. Silver nanoparticles [69]: To 1 nm triangular shaped DNA origami solution with the designed number of capture strands, 0.25 nm DNA–AgNP conjugates solution (in 1 TBE with 350 mM NaCl) was added (molar ratio of binding site to AgNP was 1:1). Then the same volume of 1 TAE-Mg2+ buffer was added to dilute the solution to reduce cross-linking and the mixture was cooled from 45 °C to 4 °C overnight. Gold nanorods [106]: To a 3 nm DNA origami solution in 0.5 TAE-Mg2+ buffer, the DNA–AuNR conjugates solution was added with a molar ratio of 1:2. Meanwhile, the final concentration of NaCl was raised to 300 mM by adding 5 M NaCl solution. Finally, the mixture was cycled between 45 °C and 30 °C for 60 h (2.5 h per cycle) to ensure sufficiently hybridization of the DNA molecules on the AuNRs with the capture strands on the DNA origami.

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5. Conclusion

[20]

DNA origami technique is now capable of constructing any arbitrary 2D and 3D nanostructures, which facilitates the engineering of nanoparticle assemblies with customized optical properties. However, most achievements focus on spherical gold nanoparticles, owing to the difficulties in DNA functionalization and precise positioning of nanoparticles with increasing number of sides and facets. On one hand, more efficient coupling methods are required to prepare DNA–nanoparticle conjugates that can be stable in the assembly mixture. On the other hand, new approaches need to be developed in order to precisely tune the spatial arrangement of the nanoparticles with different facets and branches. Anisotropic DNA functionalization of nanoparticles and the design of selective DNA origami templates that can recognize specific shapes and sizes of nanoparticles are possible solutions. Dynamic systems can also be constructed to investigate the effect of spatial changes on the plasmonic properties in real time, as well as to serve as programmable assembly line [116]. Another direction is to produce heterogeneous systems containing non-metal nanomaterials, such as quantum dots, magnetic nanoparticles, carbon nanotubes and graphene [71,73,117–119]. Several attempts have been reported to incorporate quantum dots into the nanoparticle patterns, exhibiting significantly enhanced optical properties [120,121]. The integration of bottom-up DNA origami technique with the top-down lithography shows great potential for fabricating scale-up plasmonic assemblies and solid-state devices for practical applications.

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