Shape-Controlled Synthesis of Gold Nanostructures Using DNA

Oct 2, 2014 - A small gold nanoparticle within the cavity nucleates solution-based gold deposition leading to mold filling. We demonstrate the fabrica...
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Shape-Controlled Synthesis of Gold Nanostructures Using DNA Origami Molds Seham Helmi, Christoph Ziegler, Dominik J. Kauert, and Ralf Seidel* Institute for Molecular Cell Biology, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany S Supporting Information *

ABSTRACT: We introduce a new concept that allows the synthesis of inorganic nanoparticles with programmable shape. Three-dimensional DNA origami nanostructures harboring an internal cavity are used as molds. A small gold nanoparticle within the cavity nucleates solution-based gold deposition leading to mold filling. We demonstrate the fabrication of 40 nm long rodlike gold particles with quadratic cross section and the formation of higher order assemblies of the obtained particles, which is mediated by their DNA shell.

KEYWORDS: Metal nanoparticles, seeded growth, DNA metallization, DNA nanostructures, plasmonics

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copper, and cobalt could be deposited on DNA.24 Furthermore, more complex DNA nanostructures, such as rings,25 junctions26 and spheres,18 were used as metallization templates. While the overall shape of the DNA templates could be reproduced, the obtained metal films were still rather discontinuous or inhomogeneous with many distinct grains at respectively low and high amounts of deposited metals. The key problem of the existing strategies for inorganic material deposition on DNA is that they typically rely on the introduction of a large number of small nucleation centers (such as metal ions, metal complexes, or metal nanoparticles) all over the template. In a subsequent step, the nucleation centers are enhanced and further material is deposited. The growth occurs, however, in an inhomogeneous manner. Because there is no size-control for the growing particles, grains with different diameters that are separated by differently large gaps are obtained. To overcome the problems of inhomogeneous metal deposition on DNA templates, we hereby introduce a new methodology, where metal deposition starts from single nucleation centers and size and shape of the resulting particles are controlled by a surrounding DNA mold (Figure 1a). Metal deposition at the nucleation center is carried out in a seededgrowth scheme by adding a reducing agent and a metal precursor, a method that can provide very homogeneous particles.27 Such a strategy has previously been explored using protein shells such as ferritin28,29 or the tobacco mosaic virus.30 However, the number of different naturally available protein shells is limited. Therefore, the usage of DNA-based molds promises a much larger versatility regarding possible shapes and sizes and moreover a programmable structure design.

ontrolling the morphology, composition and size of nanoscale structures is a cornerstone in material science and nanotechnology. For example, electronic circuitry on integrated chips consists of complex wiring schemes that reach nanometer dimensions even in industrial fabrication. Noble metal nanostructures with specific shapes can have remarkable properties that are exploited for applications in sensing,1 light harvesting,2,3 and spectroscopy4,5 as well as in the catalysis of chemical reactions6,7 and protein folding.8 Among the different strategies to build nanoscale structures, self-assembly based methods are particularly appealing since a large number of structures can be produced in a single synthesis reaction. The past years have seen a breakthrough in self-assembling large two- and three-dimensional structures of complex shapes in a programmable manner, where DNA is used as construction material.9,10 In addition to programmability, DNA enables the placement of functional groups and also larger objects at specific sites onto the formed structures. For example, protein binding moieties,11 chemical,12 photoactive,13,14 and amphipathic15,16 groups as well as quantum dots17,18 and metal nanoparticles19,20 could be positioned in well-determined configurations. This opened up many new applications in biophysics, nanooptics, site-specific chemistry, and plasmonics. While the field of functional DNA nanostructures astonishingly advances, a self-assembly scheme that similarly allows the programmable and versatile fabrication of nanoscopic objects from inorganic materials, such as metals, is however missing. In order to overcome this limitation, already more than a decade ago the idea has been developed to use DNA as a template for the growth of other materials. The biomolecule would then dictate the shape of the resulting structure. In first applications, linear DNA molecules were metallized, which provided elongated metal particle assemblies.21−23 Meanwhile many different materials, such as gold, silver, platinum, palladium, © XXXX American Chemical Society

Received: September 8, 2014 Revised: September 17, 2014

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Figure 1. Mold-constraint growth procedure for gold nanostructures and mold construction. (a) Scheme of the nanostructure synthesis. Molds with an inner cavity are fabricated using the DNA origami method. Capture DNA strands in the center of the cavity allow the site-specific introduction of single gold nanoparticle (AuNP) seeds carrying DNA strands with the complementary sequence. In the presence of a gold precursor and a reducing agent, the growth of the nanoparticle is initiated. Further gold deposition is blocked by the mold walls, such that the particle adopts the shape that is dictated by the mold. (b) Cartoon of the DNA mold with DNA double-helices depicted as gray cylinders and capture strands as orange spirals. (c) TEM images of the mold. (d) TEM images of the mold with bound gold nanoparticle seed. In panels c and d, the top and bottom rows show, respectively, views onto a mold side wall and along the cavity axis. All TEM images are shown at equal magnification with the scale bar corresponding to 40 nm.

Information, Figure S1). When using a 5-fold excess of AuNPs over origami molds 90 ± 3% (N = 184) of all molds carried a single seed at the central position, while the remaining molds remained empty. Attachment of two particles was not observed. Excess unbound nanoparticles could be removed through gel purification.11 Note that in the subsequently described metal growth experiments we used subsaturating amounts of nanoparticle seeds (∼0.75 AuNPs per mold) to avoid extra purification steps that would reduce the yield of functional molds. This is a simple method to avoid free particles that, in contrast to the limited amount of particle-free molds, are likely to perturb the metal deposition within the molds. For metal deposition at the AuNP seeds, we used a seeded growth procedure. The chosen combination of hydroxylamine as reducing agent and H[AuCl4] as metal precursor would not lead to spontaneous particle nucleation on its own.37 Molds with seeds were premixed with hydroxylamine. In a first approach, H[AuCl4] was subsequently added in a single step while rapidly stirring the solution. Particle growth finished after 1 min as judged from color changes of the solution. At this point, the reaction would be self-terminated due to the consumption of H[AuCl4]. TEM imaging confirmed the successful particle growth within the DNA molds (Figure 2a, see Supporting Information, Figures S2 and S3 for a larger collection of particle images). Particle growth was taking place in practically all molds containing seeds. Mold particles that attached with a side-wall to the TEM grid (providing a sideview of the particle) exhibited an elongated particle shape extending along the mold cavity. The average particle length was 39.1 ± 1.6 nm, which is in agreement with the previously determined mold length. The average particle width was 23.1 ± 0.9 nm, which is a little larger than the estimated cavity width of 16−17 nm. Apparently the growing particle expands the mold and may even penetrate into the mold walls, because all particles are still surrounded by the mold, but the mold wall appears to be thinner than before the growth (Figure 2). For a tighter control of the particle width, a stiffer mold structure11 that, for example, comprises a third or even a fourth DNA layer may be required.

We assembled a DNA mold using the DNA origami method31,32 from a 7560 nucleotide long single-stranded “scaffold strand” and hundreds of DNA oligomer “staple strands”. It resembles a hollow cuboid with a quadratic base. Its cavity has a quadratic cross-section and stretches axialsymmetrically from one quadratic face to the other (Figure 1b). The structure is formed by parallel arrangements of 64 DNA helices on a square lattice along the cavity axis.33 The widths of the cavity and the cuboid correspond to stacks of 6 and 10 DNA helices, respectively, providing a double DNA layer to form the wall of the 40 nm long structure. To allow the site-specific introduction of a nucleation center into the mold all 4 cavity faces carried a central 15 nt poly adenine capture DNA strand that extended from the 3′ end of a staple oligomer at the given position. The DNA origami molds were assembled in a one-pot reaction in which the scaffold and the staple strands are heated to 80 °C and then cooled down over the course of 15 h to room temperature (see Methods). Transmission electron microscopy (TEM) imaging confirmed the correct assembly of the hollow cuboid structure (Figure 1c). Image analysis provided an outer and inner width of 22.7 ± 0.3 and 13.7 ± 0.2 nm as well as a length of 40.0 ± 0.6 nm, respectively. This is in agreement with a distance of 2.25 nm of parallel stacked helices and a rise of 0.34 nm per bp as found for dried TEM samples.32 In solution, adjacent DNA helices within three-dimensional origami structures rather adopt distances of 2.6 to 2.9 nm as found with cryo-elecronmicroscopy33,34 and single-molecule fluorescence resonance energy transfer measurements.14 Thus, for the particle synthesis the cavity is expected to be 16−17 nm wide. As nucleation centers for further gold deposition, we used 5 nm gold nanoparticles (AuNPs) to which multiple 15 nt polythymidine strands were attached through terminal 5′-thiol modifications.19,35 The DNA-coated particles were hybridized to the four complementary capture strands located centrally in the inner cavity of the origami mold.36 The use of multiple capture strands per nanoparticle ensured highly efficient particle binding.19,35 TEM imaging confirmed the correct localization of the single AuNP seeds (Figure 1d, Supporting B

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Figure 3. Gold nanoparticles grown within origami molds through stepwise addition of H[AuCl4]. Compared to the single-step procedure (Figure 2) in each step a 5-fold lower amount of H[AuCl4] was added. Each column shows TEM images of particles obtained after a given step as indicated at the top. The column labeled with “0” shows the mold with the original AuNP seed. The top and the bottom rows show views onto a mold sidewall and along the cavity axis, respectively. The scale bar corresponds to 40 nm.

Figure 2. Gold nanoparticles grown within origami molds. The particle growth was initiated with a single step addition of H[AuCl4] to a mixture of molds and reducing agent. (a) TEM images of grown particles that adhere with a mold side-wall to the grid providing a sideview onto the particle as illustrated by the three-dimensional cartoon on the left. When the gold particles extrude from the cavity ends, they partially form aggregates of two and sometimes even more particles (see the two lower right images). The particles in these aggregates are preferentially aligned with respect to their cavity axes, because aggregation happens exclusively at the cavity ends. (b) TEM images of grown particles viewed along the cavity axis as illustrated by the cartoon on the left. The scale bars in a and b correspond to 40 nm.

example, in catalysis applications. Furthermore, such additives will optimize our procedure, for example, improve the homogeneity of the particle shape. Because capping agents also influence the actual particle growth, the reaction conditions need to be carefully tuned to establish robust protocols. After the growth, the obtained particles remained within their molds. Therefore, it should be possible to use the mold shell to site specifically functionalize the particle by hybridizing modification-bearing oligonucleotides to unpaired staple ends that extrude from the structure. To test this, we prepared two versions of gold rod particles that each carried an extruding DNA strand near each corner of one of the side faces of the mold. The four DNA strands of one version were pairwise complementary to the ones of the other version. They were distributed such that they would support a side-by-side attachment of the molds (Figure 4a). Both versions were

Although the mold cavity does not stringently stop the particle from growing once it reaches the mold wall, our results show nonetheless that the mold imprints its shape on the particle. This is furthermore supported by the observed shapes of the particles when viewed along the cavity axis (Figure 2b). They clearly exhibited squarelike shapes as expected from the mold cross-section. The corners of the squares appeared partially roundish. This may be due to the mold expansion that was inferred from the increased particle widths (see above). Gold particles that extrude from the mold ends partially aggregate to each other (Figure 2a). This is due to the absence of a capping agent in the growth solution, such that the gold surfaces remain unprotected and try to minimize their surface energy by adhering to another particle. In agreement with this, the observed aggregation happens only at cavity ends but not at mold side walls. Because the amount of available H[AuCl4] is supposed to limit the gold growth, tuning of the H[AuCl4] to AuNP seed ratio would allow control of the size of the finally obtained particle. To demonstrate this we applied a 5-step growth procedure, where we added in each step a 5-fold lower amount of H[AuCl4] compared to the single-step procedure. Samples for TEM imaging were prepared after each step. Obtained images confirmed the controlled particle growth (Figure 3). Initially, round particles with a diameter smaller than the width of the mold cavity were observed. Once the particle dimensions reached the cavity width, the particle adopted at first a cubic and subsequently an elongated cuboid shape with a squarelike cross-section. This suggests that the rigid mold walls slow down the particle growth perpendicular to the cavity axis. We note that further gold growth out of the cavity ends (e.g., to form gold dumbbells) was not supported by our seeded growth protocol. Upon addition of more H[AuCl4], particle aggregation (see above) was too strong. The use of capping agents will in the future avoid this problem and eventually support the removal of the whole origami shell, as desired, for

Figure 4. Higher-order assembly of the grown gold rods mediated by the mold shell. (a) Scheme of the side-by-side dimerization of two mold-surrounded particles. Four DNA single strands that extrude in the corners at one mold side (red) mediate the binding to a second mold that carries four single strands with the complementary sequence (green). (b) TEM images of particle dimers that formed after the growth by mixing both types of mold carrying particles. Views onto the mold side walls (top right) and along the mold cavities (all other images) are shown. If one of the two molds lacked a seed, a half-filled mold assembly was obtained (lower right). The scale bar corresponds to 50 nm.

mixed after nanoparticle growth and allowed to hybridize to each other at 40 °C. The expected particle dimers were obtained (Figure 4b, Supporting Information, Figure S4) with an efficiency of 69 ± 8% (N = 45). This demonstrates that the prepared particles can be site-specifically modified and undergo higher order self-assembly reactions past the metallization process. The obtained efficiency seems to be typical for this kind of dimer formation and appears not to be reduced by the C

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Figure 5. Higher-order mold assembly with posterior particle growth. (a) Side-by-side dimers obtained through hybridization of complementary single-stranded DNA overhangs in the corners of a mold side-wall (see cartoon and also Figure 4). TEM images show mold dimers with AuNP seeds when viewed along the mold cavities (top) or onto one mold side (bottom) (b) Gold particle dimers grown from mold dimers in a side-by-side arrangement. Views onto the mold side walls (top right) and along the mold cavities (all other images) are shown. (c) Head-to-tail dimers (see cartoon) obtained by 2 bp staple overhangs that penetrate from one mold into the other (see Methods). TEM images show mold dimers with AuNP seeds (d) Gold particle dimers grown from mold dimers in a head-to-tail arrangement. All scale bars correspond to 50 nm. TEM images in panels b and d at the bottom right show mold dimers that carried only a single seed. This reveals the possible expansion of the mold during particle growth (see panel d).

expansion of the molds. We therefore excluded them from our analysis. In summary, we demonstrated the successful synthesis of gold nanoparticles whose shape is determined by a DNA nanostructure-based mold. In particular, we achieved the synthesis of nanorods with a squarelike cross-section and an aspect ratio of 1.7. However, we expect that our method will be readily applicable to other structure designs and shapes. Our work is a promising concept in order to establish a new general scheme for the solution-based synthesis of inorganic nanostructures with freely programmable shapes. This contrasts previous nanoparticle synthesis schemes that required the elaborate development of specialized protocols to achieve particles with different shapes. Future efforts in developing our methodology should concentrate on fabricating differently shaped particles and on adapting it to different materials. Beyond the synthesis of small particles that in part can already be produced using standard methods, the capability to obtain higher order assemblies of either molds or final particles is of particular interest. Higher order assembly was demonstrated in this work by producing side-by-side and head-to-tail dimers before and after the metal growth procedure. Using the recent advances in DNA nanotechnology much larger and more complex heterostructures from different materials should however be achievable. For example, electronic circuit-like structures could be fabricated by assembling complex continuous cavity structures that provide connectors and junctions. Electronically active elements such as quantum dots or carbon nanotubes could also be site-specifically integrated. Overall, we are convinced that our mold-based DNA metallization scheme will inspire new applications in the area of solution-based nanostructure selfassembly. Methods. DNA-Origami Design, Assembly, and Analysis. The DNA origami mold (Supporting Information, Figure S6) has been designed using CaDNAno.38 Reverse-phase cartridgepurified oligonucleotides for the DNA origami objects were purchased from Eurofins MWG Operon. Single-stranded scaffold DNA was produced as described elsewhere.32 The one-pot assembly reaction was performed as follows: 10 nM scaffold p7560 was mixed in folding buffer containing 5 mM Tris-HCl, 1 mM EDTA and 11 mM MgCl2 (pH 8.0) with unpurified staple strands and capture strands in a molar ratio of 1:10:1 (per individual sequence). The reaction was heated to 80 °C for 5 min and cooled to 25 °C over 15 h using a

presence of the grown particle in the inside of the mold (see dimerization of empty mold below). We next tested whether it is possible to grow metal nanoparticles on preassembled higher order structures of molds. We assembled side-by-side dimers of molds with attached AuNP seeds (Figure 5a). Mold dimers formed with an efficiency of 50 ± 6% (N = 84). This is lower than for the dimerization of grown particles, though this difference is still within the statistical uncertainty. After the preassembly of mold dimers, we subjected them to gold deposition. Similar to the postgrowth assembly, we obtained the expected side-by-side dimers of our rodlike particles (Figure 5b, Supporting Information, Figure S5a). Furthermore, we assembled headto-tail dimers (see Methods), in which an expanded cavity of twice the length is formed such that the resulting continuous mold carries two AuNP seeds (Figure 5c, Supporting Information, Figure S5b). These dimers form with a much higher efficiency of 94 ± 3% (N = 80). When growing gold particles in these structures, extended rods that were twice as long as the particles grown in single molds were obtained (Figure 5d, Supporting Information, Figure S5b). The particles typically connected rather tightly to each other. If an AuNP seed was missing in one of the mold parts, then gold growth occurred only in the mold part that carried the seed (Figure 5d, bottom right). TEM images for these “half-filled” molds also revealed the expansion of the seed-containing mold-part during particle growth, while the seed-free mold shrinks slightly upon sample drying below its original size. The quasi-continuous head-to-tail particle dimers (Figures 5c,d) additionally support that the mold is influencing the particle shape primarily by providing a stiff boundary that hinders further particle expansion. An alternative explanation would be a limited diffusion of gold precursor and reducing agent across the side walls. In this case, because the two growing nucleation centers clog the mold cavity in the progress of the metallization process an inhibited growth of both particles toward the center of the mold dimer would be expected. This is however not observed. It should be noted that we also tested a head-to-tail mold dimer formation after the gold particle growth (as in Figure 4). Such dimers formed. However, they could not be distinguished unambiguously from dimers that formed through gold aggregation (see Figure 2a). Also the mold shell seemed to be often interrupted at the dimer interface due to the steric repulsion between the two gold particles or due to different D

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as DNA-functionalized AuNPs were then mixed in a 1:1:2 molar ratio. The solution was supplemented with 300 mM NaCl and was subjected to the slow annealing reaction described for AuNP attachment to the monomeric molds. Seeded-Growth of Gold Nanoparticles within DNA Molds. For the growth experiments, the mold concentration was adjusted with folding buffer (see above) such that 4.5 nM seeds were present in solution and hydroxyl amine (NH2OH) was added to a final concentration of 1.35 mM. The seeded growth of gold nanoparticles within the molds was adapted from literature.37 For the single-step procedure, growth was initiated by injecting a single time 0.9 μL of 25 mM H[AuCl4] into 99.1 μL of the NH2OH containing mold solution. For the multistep procedure, five times 2 μL of 2.25 mM H[AuCl4] were subsequently injected into 90 μL of the NH2OH containing mold solution. During each injection the solution was vigorously stirred and subsequent particle growth was carried out for 1 min. Afterward TEM samples were prepared. Dimer Formation after Particle Growth. Each type of monomer with an attached seed was subjected in a separate reaction to a single-step gold growth procedure. Both monomer types were then mixed in a 1:1 ratio and allowed to hybridize to each other at 40 °C for 1 h.

nonlinear temperature ramp with the slowest temperature decrease occurring between 55 to 45 °C. The folded objects were investigated with gel-electrophoresis (1% agarose gel, 0.5× TBE, 11 mM MgCl2, 3.5 V/cm). Subsequently, the molds were purified twice using 100 kDa MWCO Amicon Ultra 0.5 mL filters (Merck-Millipore, Darmstadt, Germany). The sample was pipetted into the filter column, filled up to 500 μL with folding buffer, and centrifuged at 14 000g for 5 min. Subsequently, the filtrate was discarded. After a repeat of the purification step, the filters were turned upside down and centrifuged for 3 min at 1000g into a new collection tube. The concentration was then determined from the absorbance of the sample at 260 nm using a NanoPhotometer (Implen). For TEM imaging, 2−3 μL of a diluted origami sample solution (1−2 nM) was applied to glow-discharged carbon-coated grids. The sample was subsequently stained using a filtered 2% solution of uranyl formate in 5 mM NaOH for 2 min. TEM imaging was performed on a Zeiss Libra 120 transmission electron microscope at 80 kV. Mold and particle sizes were quantified from TEM images using ImageJ.39 Size errors were given as standard deviations. Efficiency errors were calculated from the standard deviation of the binomial distribution.40 DNA Functionalization of AuNPs. To prepare oligonucleotide-modified AuNP seeds 5 nm AuNPs (Sigma-Aldrich) were subjected to a ligand exchange with bis(p-sulfonatophenyl) phenylphosphine (BSPP) to increase the colloidal stability at high particles concentrations.19,35 Five milligrams of BSPP dihydrate dipotassium salt was added to 15 mL of colloidal AuNPs (5.5 × 1013 particles/ml) and the mixture was stirred in the dark for 20 h at room temperature. Solid NaCl was added while stirring the solution until the color changed from red to purple. The solution was centrifuged at 3000 rpm for 30 min, and the supernatant was carefully removed. AuNPs were then resuspended with 1 mL of 2.5 mM aqueous solution of BSPP. Two milliliters of methanol were added and the solution was subjected to another round of centrifugation. After resuspending the AuNP pellet in 1 mL of 2.5 mM BSPP, the concentration of the AuNPs was estimated from the absorbance at 520 nm. For DNA functionalization of the stabilized AuNPs, 15 nt polythymidine oligonucleotides carrying a 5′-thiol modification were incubated in 20 mM tris(carboxyethyl) phosphine hydrochloride (TCEP) to reduce the disulfide bonds.19,35 The oligonucleotides were purified using a G-25 size exclusion column (GE Healthcare) and incubated with the stabilized AuNPs in a 500:1 ratio. Three-hundred and fifty millimolar NaCl was gradually added at room temperature over a time course of 48 h to increase the coverage of oligonucleotides on the surface of the AuNPs.41 The AuNP−DNA conjugates were filtered four times using 100 kDa MWCO Amicon Ultra 0.5 mL filters using the electrophoresis buffer to remove the unbound oligonucleotides. Finally, the particle concentration was estimated from the absorbance at 520 nm. Nanoparticle Seed Attachment. The DNA-functionalized AuNPs were mixed with the purified DNA origami molds at a molar ratio of 5:1 or 0.75:1 (see main text) and 300 mM NaCl. The mixture was slowly heated to 40 °C and afterward cooled down to 23 °C over 24 h to allow hybridization of the AuNPs with the complementary capture strands on the mold. Mold Dimer Formation. Each type of monomer forming the mold dimer (see Supporting Information, Figures S6 and S7 for the design details of side-by-side and head-to-tail dimers) was assembled and purified separately. Both monomer types as well

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ASSOCIATED CONTENT

* Supporting Information S

Overview electron-microscopy micrographs as well as design files for the origami mold construction. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +49 251 83 23920. Present Address

(C.Z.) Physical Chemistry, Technische Universität Dresden, Bergstr. 66b, 01062 Dresden, Germany. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge stimulating discussions with Professor Alexander Eychmü ller, support during figure preparation by Felix Kemmerich, as well as the group of Martin Bähler for access to TEM imaging. This work was supported by an ERC starting Grant (261224) and the Transregional Collaborative Research Center TRR 61 (project C8).

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