Self-Assembly of Luminescent Ag Nanocluster-Functionalized

Article pubs.acs.org/Langmuir

Self-Assembly of Luminescent Ag Nanocluster-Functionalized Nanowires Ron Orbach,‡ Weiwei Guo,‡ Fuan Wang, Oleg Lioubashevski, and Itamar Willner* Institute of Chemistry, Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel S Supporting Information *

ABSTRACT: Two different methods to self-assemble red- or yellow-luminescent nucleic acids-stabilized Ag nanoclusters (NCs) nanowires are presented. By one method, the autonomous hybridization−polymerization process between two nucleic acids leads to polymer chains consisting of sequence-specific loops for the stabilization of the red- or yellow-emitting Ag NCs. By the other method, the nucleic acid-triggered hybridization chain reaction (HCR) involving the cross-opening of two functional hairpins leads to sequence-specific DNA loops and a nucleic acid scaffold that stabilize the respective red- or yellow-emitting Ag NCs. The micrometer-long luminescent Ag NC-functionalized nanowires are imaged by AFM and confocal microscopy.

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INTRODUCTION

The synthesis of sequence-specific DNA-stabilized metal nanoclusters, NCs, particularly Ag NCs, attracted substantial interest in recent years.35−37 For example, cytosine-rich nucleic acids act as templates for the stabilization of Ag NCs.38,39 The Ag NCs consist of a few silver atoms and reveal interesting photophysical properties reflected by tunable luminescence properties that are controlled by the sizes of the Ag NCs and the respective protecting nucleic-acid ligands.40−42 These luminescent Ag NCs found different sensing applications, such as the analysis of ions43,44 or biomarkers,45 or the development of biosensors for DNA,46,47 aptamer-substrate complexes,48,49 and for probing enzyme activities.50 Other applications of the Ag NCs have involved cell imaging51 and the preparation of luminescent hydrogels.52,53 The availability of autonomous polymerization process of DNA nanowires suggests that by appropriate programming of the base sequences of the primary nucleic acid subunits, nanowires consisting of repeat units that stabilize Ag NCs could be generated. Thus, the deposition of the size-dependent Ag-NCs in the self-assembled polymerized nanowires may lead to tunable luminescent nanowires. Here we report on the

The base-sequence encoded in nucleic acids provides substantial structural and functional information. This may include instructive structural information, such as sequence-specific duplex formation, ion- or pH-stimulated self-assembly of Gquadruplexes1,2 or i-motif3,4 structures. Base-sequence-guided functional features of DNA may include specific recognition properties (aptamers),5−7 catalytic functions (DNAzymes, ribozymes),8−10 reactions with enzymes (nicking or endonuclease)11,12 or sequence-specific binding of proteins.13,14 These unique functions of oligonucleotides were extensively used to develop DNA-based sensors,15−18 to construct DNA machines,19,20 to assemble DNA nanostructures,21−24 and to implement DNA as functional materials for computing.25−28 Different polymerization processes involving DNA scaffolds were developed, and these led to programmed nanostructures. For example, the rolling circle amplification (RCA) process yields micrometer-long chains composed of replicated units of the circular template.29,30 Similarly, the hybridization chain reaction (HCR), triggered by the cross-opening of two hairpin nucleic acids, leads to the formation of polymerized nucleic acid wires.31,32 By the sequence-specific binding of complementary nucleic acids to the RCA-generated wires, the specific binding of nanoparticles33 or proteins34 was demonstrated. © 2013 American Chemical Society

Received: July 28, 2013 Revised: September 16, 2013 Published: September 24, 2013 13066

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Microscopy. Atomic force microscopy (AFM) images were recorded using a Nanoscope 3A controller (Digital Instruments/ Veeco Probes, Plainview, NY, United States) with NSC 15 AFM tips (Mikromasch, Tallinn, Estonia) using the tapping mode at their resonant frequency. The DNA sample was deposited on a freshly cleaved mica surface (Structure Probe Inc., West Chester, PA, United States), dried in air, and gently washed with double-distilled water (DDW). Images were analyzed using the WsXM SPIP software (Nanotec, Inc., Madrid, Spain). Confocal microscopy imaging was performed using a Leica SP5 confocal microscope (Germany) equipped with a 63×/1.4 oil immersion objective. Red-emitting systems were excited at 561 nm with emission in the range of 600−700 nm. Yellow-emitting systems were excited at 514 nm with emission in the range of 530−600 nm. Before adding a drop of a fresh fluorescent nanowires solution, the glass slides were first washed with distilled water, followed by an ethanol and acetone wash, and then were UV/ozone cleaned, using a T1O × 10/ OES/E UV/ozone chamber from UVOCS, Inc. (USA). Subsequently, the glass slides were incubated in 2% aminopropyltriethoxysilane for 30 min, and heated to 110 °C for 10 min to generate a positively charged surface of amino monolayer.

synthesis of sequence-specific nanowires that provide templates for the stabilization of Ag NCs. This leads to the generation of DNA nanowires exhibiting tunable luminescent functions. Two different pathways involving the hybridization−polymerization reaction or the hybridization chain reaction are implemented to prepare functional template nanowires.

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MATERIALS AND METHODS

Materials. Phosphate buffer, sodium nitrate, sodium borohydride, silver nitrate and magnesium nitrate were purchased from SigmaAldrich. HPLC-purified DNA oligonucleotides were purchased from Integrated DNA Technologies Inc. (Coralville, IA, United States). All the solutions were prepared with ultrapure water purified by a NANOpure Diamond system (Barnstead International, Dubuque, IA, United States). DNA Sequences. (1) 5′-CCTGACTCCTGAGGAGAAGCACAACTAACT-3′ (2) 5′-CCTGACTCCTGTGGAGAAGCACAACTAACT-3′ (3) 5′-CTTCTCCACCCCCCCAGGAGTCAGGAGTTAGTTGTG3′ (4) 5′-CTTCTCCACACCCCCCGGAGTCAGGAGTTAGTTGTG3′ (5) 5′-ACAACTAATCCTGACTCCTGAGGAGAAGTCTTACATACTTCTCCACAGGAGTCAGG-3′ (6) 5 ′ - C T T C T C C A C C C C C C C A G G A G T C A G G A T TAGTTGTCCTGACTCCTGTGGAGAAGTATGTAAGA-3′ (7) 5′-CTTCTCCTCAGGAGTCAGGATTAGTTGT-3′ (8) 5′-ACAATAATCCTGACTCCTGTGGAGAAGCTTAATCACTTCTCCTCAGGAGTCAGG-3′ (9) 5′-CTTCTCCACACCCCCCGGAGTCAGGATTATTGTCCTGACTCCTGAGGAGAAGTGATTAAG-3′ (10) 5′-CTTCTCCACAGGAGTCAGGATTATTGT-3′ Hybridization−Polymerization Reaction System. Equimolar amounts of DNA strands (1) and (3) or (2) and (4) were mixed in phosphate buffer to a final concentration of 2 μM for each strand. For the hybridization−polymerization reaction of the DNA strands, each mixture solution was heated up to 85 °C for 15 min, and then slowly cooled down to room temperature overnight. Next, AgNO3 (3:1 molar ratio with respect to the DNA) was added into the DNA mixture solution, and reduced for 5 h by adding NaBH4 (1:1 ratio with respect to AgNO3) to form Ag NCs. The red-emitting nanowires were formed in a high-salt buffer (10 mM phosphate, 200 mM sodium nitrate, 1 mM magnesium nitrate, pH 7.0), while the yellow-emitting nanowires were formed in a low-salt buffer (20 mM phosphate, 1 mM magnesium nitrate, pH 7.0). Hybridization Chain Reaction (HCR) System. Each of the strand solutions consisting of (5), (6) (8) or (9) was heated to 85 °C for 15 minutes and then placed in an ice bath for 15 minutes, followed by incubation at room temperature for 1 hour, to yield the respective hairpins stabilized structures. Subsequently, AgNO3 (3:1 molar ratio with respect to the DNA) was added to the solutions that included hairpins (6) or (9), followed by the addition of the hairpins solutions (5) or (8), respectively. Finally the analyte strand (7) or (10) was added at the appropriate concentrations to the respective mixtures and kept at room temperature overnight. Then, NaBH4 (1:1 molar ratio with respect to AgNO3) was added to the respective systems and allowed to react for five hours to form the Ag NCs. For the red-emitting Ag NCs system, the hairpins (5) or (6) were generated in a high-salt concentration buffer solution (10 mM phosphate, 200 mM sodium nitrate, 1 mM magnesium nitrate, pH = 7.0) For the yellow-emitting Ag NCs system, the hairpins (8) or (9) were generated in a low-salt concentration buffer solution (20 mM phosphate, 1 mM magnesium nitrate, pH = 7.0) Fluorescence Measurements. Light-emission measurements were recorded by a Cary Eclipse fluorimeter (Varian Inc.) using a 1cm path length quartz cell. Fluorescence intensities were measured and normalized as F/Fmax.

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RESULTS AND DISCUSSION Figure 1A depicts one approach to synthesize the Ag NCsmodified DNA nanowires. The system consists of the single-

Figure 1. (A) Autonomous hybridization−polymerization process that leads to chains consisting of sequence-specific nucleic acid hairpin structures on DNA scaffolds for the deposition and stabilization of luminescent Ag NCs. (B) Excitation (I) and luminescence (II) spectra of the red-emitting Ag NCs nanowires. (C) Excitation (I) and luminescence (II) spectra corresponding to the yellow-emitting Ag NCs nanowires.

stranded nucleic acids (1) or (2) and the cytosine-rich sequences (3) or (4). The components (1) and (3) or (2) and (4) include the appropriate complementarities to stimulate the autonomous hybridization−polymerization reaction to yield the DNA nanowires composed (1)/(3) or (2)/(4). The loop regions of the resulting nanowires include the base sequences that can stabilize specific Ag NCs.42 While the loop of (3) includes the sequence for stabilizing the red-emitting Ag NCs (λem = 635 nm) together with (1), the loop region of (4) consists of the sequence that stabilizes the yellow-emitting Ag NCs (λem = 570 nm) together with (2). Thus, by the reaction of the respective nanowires templates with Ag+/NaBH4, the synthesis of emitting nanowires exhibiting controlled luminescence features is expected. The luminescence properties of the (1)/(3) nanowires functionalized with the red-emitting Ag NCs are shown in Figure 1B. The excitation spectrum reveals a maximum value at λex = 575 nm, and the emitted luminescence is observed at λem = 13067

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(1)/(3) nanowires. Micrometer-long wires are observed with the height of ∼1.2 nm, corresponding to the height of the duplex structure of the DNA. Figure 2B depicts a confocal microscopy image of the resulting red-emitting Ag NCs (1)/(3) nanowires. Similarly, the AFM and confocal microscopy images of the Ag NCs stabilized on the (2)/(4) nanowires are shown in Figure S1, Supporting Information. The formation of luminescent Ag NCs nanowires has been further implemented for the development of DNA analytetriggered HCR sensing system. Toward this goal, the two hairpins, (5) and (6) were used to activate, in the presence of the single-stranded nucleic acid analyte, (7), the HCR, Figure 3. In

635 nm. The luminescence spectrum is consistent with the luminescence properties of the Ag NCs stabilized by the monomer nucleic acid consisting of the loop associated with (3) hybridized with (1). Similarly, Figure 1C depicts the excitation and luminescence spectra of the Ag NCs deposited onto the (2)/(4) nanowires. The yellow excitation spectrum reveals a maximum value at λex = 520 nm, and the emitted luminescence is observed at λem = 570 nm, consistent with the luminescence spectrum of the Ag NCs stabilized by the monomer nucleic acid consisting of the loop sequence of (4) hybridized with (2). The resulting nucleic-acid-stabilized Ag NCs nanowires were further imaged by AFM and confocal fluorescence microscopy. Figure 2A shows the AFM image of the Ag NCs-functionalized

Figure 3. Autonomous nucleic acid (target)-induced activation of the hybridization chain reaction that involves cross-opening of two functional hairpin structures that lead to DNA chains, consisting of sequence-specific hairpins on DNA scaffolds that stabilize the (A) redor (B) yellow-emitting Ag NCs.

this system, the hairpin (5) includes in its stem region the recognition sequence I for binding the analyte (7), and also the “caged” domain I1′ and domain I2′ in hairpin (6). In addition, hairpin (6) includes in its stem region the sequence II that is complementary to the inactive “caged” structure, domain II′, in hairpin (5). Thus, in the presence of the analyte DNA (7), the hairpin (5) is opened (through hybridization with (7)), and this triggers the autonomous, isothermal, cross-opening of hairpins (6) and (5), leading to the formation of DNA nanowires, consisting of the base-sequence for the stabilization of the redemitting Ag NC nanowires.42 Treatment of the resulting nanowires with Ag+/NaBH4 leads to the deposition of sequence-stabilized Ag NCs on the nanowires. Figure 4A depicts the luminescence spectra of the nucleic acid-stabilized Ag NCs nanowires (λex = 575 nm) formed upon the treatment of the hairpins (5) and (6) with different concentrations of the analyte (7). As the concentration of (7) increases, the luminescence of the Ag NCs is intensified, consistent with the enhanced activation of the cross-opening of the hairpin units (5) and (6), and the formation of self-assembled nucleic acid-sequences

Figure 2. (A) AFM image of the red-emitting Ag NCs chain. (Inset) Cross-section analysis of the resulting Ag NCs chains. (B) Confocal microscopy image of the red-emitting Ag NCs wire. 13068

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microscopy images of the yellow-emitting Ag NCs-functionalized nanowires, respectively. In conclusion, the present study has demonstrated the triggered autonomous, isothermal self-assembly of DNA nanowires that provide functional templates for the deposition of sequence-stabilized Ag NCs exhibiting controlled luminescence properties. Furthermore, our study coupled between sensing phenomena and the synthesis of luminescent Ag NCsfunctionalized nanowires by demonstrating the analyte-triggered cross-opening of two hairpins and the autonomous formation of functional DNA nanowires acting as templates for the Ag NCs. The HCR process was extensively implemented for sensing. Thus, the successful synthesis of the red- and yellow-emitting nanowires by two different analytes paves the way to develop multiplexed DNA (or aptamer) analysis schemes based on luminescent nucleic acid/Ag NCs systems. By the implementation of other sequence-specific metal NCs (e.g., Au, Cu) the parallel detection of several analytes may be envisioned.

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ASSOCIATED CONTENT

S Supporting Information *

AFM and confocal images of the yellow-emitting Ag NCs nanowires formed by hybridization−polymerization. This material is available free of charge via the Internet at http://pubs. acs.org.

Figure 4. (A) The luminescent spectra corresponding to the redemitting Ag NC chains generated upon the activation of the HCR in the presence of different concentrations of strand (7): (a) 100 nM (b) 50 nM (c) 10 nM (d) 1 nM (e) 0 nM. (B) AFM image of the red-emitting Ag NCs wires induced by strand (7), 10 nM. (C) Confocal microscopy image of the resulting Ag NCs wire, induced by strand (7), 10 nM. (D) The luminescent spectra corresponding to the yellow-emitting Ag NC chains generated upon the activation of the HCR in the presence of different concentrations of strand (10): (a) 200 nM (b) 100 nM (c) 10 nM (d) 1 nM (e) 0 nM. (E) AFM image of the yellow-emitting Ag NCs wires induced by strand (10), 10 nM. (F) Confocal microscopy image of the resulting Ag NCs wires, induced by strand (10), 10 nM.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Author Contributions ‡

R.O. and W.G. contributed to this paper equally.

Notes

The authors declare no competing financial interest.

stabilizing the Ag NCs on the resulting nanowires. Figure 4B shows representative AFM image of the Ag NCs-stabilized nanowires (5)/(6), formed upon the (7)-triggered crossopening of the hairpins. Micrometer-long nanowires are formed, where the height of the double-stranded nanowires corresponds to ca. 1.2 nm. Similarly, Figure 4C shows the confocal microscopy image of the resulting red-emitting Ag NCsmodified nanowires. In analogy, the cross-opening of hairpins (8) and (9) by the analyte (10) was used to generate the yellowemitting Ag NCs-stabilized nanowires, Figure 3B. In this system, the hairpin (8) includes the recognition sequence III for the analyte (10), and for the hybridization with the “caged” domain III1′ and domain III2′ in hairpin (9). Hairpin (8) includes also the “caged” sequence IV′ for opening hairpin (9) by the hybridization with domain IV. Thus, in the presence of the analyte (10), cross-opening of hairpins (8) and (9) proceeds to yield DNA nanowires consisting of the base-sequence for the stabilization of the yellow-emitting Ag NCs nanowires. Figure 4D shows the luminescence spectra of the yellow-emitting nanowires (λex = 520 nm) generated upon the treatment of the hairpins (8) and (9) with different concentrations of the target DNA, (10). As the concentration of (10) increases, the luminescence generated by the nanowires is intensified, consistent with the enhanced cross-opening of the hairpins, and the formation of the nanowires for templating the Ag NCs. Figure 4(E) and 4(F) display representative AFM and confocal

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ACKNOWLEDGMENTS

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REFERENCES

This research is supported by the Volkswagen Foundation, Germany.

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