pH-Responsive Nanoparticle Superlattices with Tunable DNA Bonds

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pH-Responsive Nanoparticle Superlattices with Tunable DNA Bonds Jinghan Zhu,†,‡,⊥ Youngeun Kim,†,‡,⊥,∥ Haixin Lin,‡,§ Shunzhi Wang,‡,§ and Chad A. Mirkin*,†,‡,§ †

Department of Materials Science and Engineering, ‡International Institute for Nanotechnology, §Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States S Supporting Information *

explore and manipulate optoelectronic properties in epitaxially grown crystalline thin films and free-standing single crystals.11 Indeed, learning how to chemically control the interactions of the nanoparticles within such superlattices is of paramount importance to eventually make use of them in optically active devices. Changes in pH have been used as the stimulus to effect actuation in molecular motors,12−14 biological sensors,15,16 and a variety of molecular switchable DNA-based architectures,17,18 and although pH (i.e., proton environment) is one of the most extensively used triggers to effect both chemical and physical changes in material-based systems in general,14,19,20 it has yet to be explored in the context of DNA-driven crystal engineering strategies. In this work, we explore how pH-responsive i-motifs can be synthetically incorporated into DNA bonding elements to control nanoparticle lattice formation, crystallization path, and crystal structure. An i-motif (Figure S1) is a cytosine-rich DNA strand that forms a quadruplex structure in acidic conditions (e.g., pH 5), but extends into a single strand configuration under basic conditions (e.g., pH 8).14 Therefore, with an i-motif, one can interchangeably access a “contracted” or an “extended” state simply by changing pH.13,18 We hypothesized that in a nanoparticle superlattice, the change in DNA length would directly translate into a controllable change in interparticle distance, resulting in a programmable change in the crystal lattice constant. In addition, we explored how the folding and unfolding of an i-motif can be used to completely break one set of bonds while initiating the formation of a new set, thereby altering the crystallization path and ultimate crystal structure. In proof-of-concept experiments, pH-responsive PAEs were constructed by first functionalizing colloidal gold nanoparticles with a dense shell of “anchor” oligonucleotides bearing a terminal propylthiol (Figure S2).4 Complementary “linker” oligonucleotides were then hybridized to the “anchor” strands such that each PAE had its own unique set of linker strands. A typical linker strand was composed of three different regions: (i) a recognition region, an 18-base pair sequence fully complementary to the anchor strand, (ii) a spacer region, through which the overall length of the linker strand is modulated, and (iii) a sticky end region, a short single-stranded DNA that enables bonding between PAEs via hybridization. In this work, we synthesized and explored two types of pHresponsive PAEs, expandable and reconfigurable, by incorporating an i-motif structure at two distinct positions in the spacer region within the linker DNA (Figure S3).

ABSTRACT: Stimuli-responsive nanomaterials with reconfigurable structures and properties have garnered significant interest in the fields of optics, electronics, magnetics, and therapeutics. DNA is a powerful and versatile building material that provides programmable structural and dynamic properties, and indeed, sequencedependent changes in DNA have already been exploited in creating switchable DNA-based architectures. However, rather than designing a new DNA input sequence for each intended dynamic change, it would be useful to have one simple, generalized stimulus design that could provide multiple different structural outputs. In pursuit of this goal, we have designed, synthesized, and characterized pHdependent, switchable nanoparticle superlattices by utilizing i-motif DNA structures as pH-sensitive DNA bonds. When the pH of the solution containing such superlattices is changed, the superlattices reversibly undergo: (i) a lattice expansion or contraction, a consequence of the pH-induced change in DNA length, or (ii) a change in crystal symmetry, a consequence of both pH-induced DNA “bond breaking” and “bond forming” processes. The introduction of i-motifs in DNA colloidal crystal engineering marks a significant step toward being able to dynamically modulate crystalline architectures and propagate local molecular motion into global structural change via exogenous stimuli.

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s a highly programmable material, DNA has proven useful for chemically arranging nanoscale building blocks into complex and functional colloidal crystalline materials.1−3 The basis for such materials, programmable atom equivalents (PAEs), are typically composed of a nanoparticle core with synthetic oligonucleotides densely coating the surface so they are forced into an upright orientation. PAEs are unique material building blocks, in which the core “atom” identity (nanoparticle shape, size, and composition) and “DNA bonds” (sequence, length, strength, and density) can be independently tuned.4 Importantly, the sequence-specific interactions between oligonucleotides allow one to program the assembly of nanoparticle superlattices with control over the crystal lattice parameter,3 symmetry,4 and habit.5 In certain cases, the DNA that defines such superlattices can be intentionally designed to be stimuli-responsive, resulting in structures that respond to small molecule chemical cues (oligonucleotides6,7 or intercalators8) or changes in osmotic pressure9 or dielectric media.10 These stimuli can lead to profound changes in the structure or crystallization path, and have been used to systematically © XXXX American Chemical Society

Received: March 12, 2018

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DOI: 10.1021/jacs.8b02793 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society In the first case of pH-responsive PAEs, an i-motif structure was incorporated in the spacer region closer to the particle, such that the overall length of the linker was adjustable (Figure 1A). A 20-base pair duplexed sequence was inserted in the

increase bond rigidity by forming duplexed DNA.13,14,18 We hypothesized that a combination of pH and i-comp strands would result in significant structural changes within the superlattice and move the pH window over which the stimuli-induced change takes place. In order to evaluate this hypothesis, two classes of pH-responsive assemblies were prepared. The first was with i-motifs to form the fcc architecture as previously described. The second was treated with i-comp strands (Figure 2A). It is important to note that three bases were altered within the sequence of the i-comp strand to prevent it from forming a G-quadruplex structure (Figure S10C and Table S3).

Figure 1. (A) Scheme showing how an i-motif structure is incorporated in the spacer region closer to the nanoparticle, such that the overall length of the linker is changed by controlling the solution pH (i.e., the i-motif unfolds upon increase in pH (basic conditions; pH 8) and folds at low pH (acidic conditions; pH 5)). (B) SAXS data show the formation of fcc crystals in the presence of i-motif linkers upon assembly. Measurements in the expanded (i, iii, v) and contracted states (ii, iv) confirm that ordered superlattices can be reversibly toggled between conformations upon pH change.

spacer region following the i-motif, providing enough space between the i-motif and the sticky end, such that the steric bulk of the i-motif did not inhibit formation of colloidal crystals (Figure S3A).21 The i-motif-containing PAEs with selfcomplementary sticky ends were assembled into a facecentered-cubic (fcc) crystal structure. PAE superlattices with i-motifs exhibited similar melting temperatures at different pH levels (Figure S4). Small angle X-ray scattering (SAXS) data showed well-resolved patterns corresponding to fcc crystals (Figure S5). Taken together, these results confirmed that the bulkiness of the i-motif caused negligible steric hindrance to the assembly of PAEs, and ordered superlattices can indeed be constructed. The PAE superlattices with i-motif linkers were then studied to determine if they could be toggled between two different states (“contracted” and “expanded”) within an assembled lattice structure. At pH 8, the self-complementary PAEs formed well-defined fcc crystals with a lattice constant of 69.6 nm. Upon addition of HCl to reach pH 5, the overall lattice contracted to a lattice constant of 59.6 nm while still retaining its overall crystal symmetry. To reverse the reaction, NaOH was added to raise the pH to 8, which resulted in a concomitant increase in lattice constant to 69.8 nm. This reversible change in lattice constant was confirmed for two full cycles in which no crystal symmetry change was observed with little to no change in the crystalline domain size (Figures 1B and S6). A similar approach was applied to a binary set of pH-responsive PAEs with complementary sticky ends, which were assembled into body-centered-cubic (bcc) crystals. In this example, the bcc crystals were reversibly toggled between two different lattice constants, 56.7 nm (pH 8) and 50.6 nm (pH 5) (Figure S8). The difference in lattice constant change for the two different examples is primarily a reflection of the different crystal symmetries. In addition to pH, DNA strands complementary to the imotif (“i-comp” strands) can be used to regulate structure and

Figure 2. (A) Using the same initial set of PAEs, two separate scenarios were experimentally compared: one in which the i-motif linker remained unmodified, and the other that was treated with icomp strands. (B, C) Structural changes in pH-responsive PAEs ((B) with and (C) without i-comp strands) were characterized via SAXS at different pH levels. (D) PAEs with i-comp strands exhibited the greatest change in lattice constants at a lower pH value in comparison to those without i-comp strands.

At pH 5, both assemblies were fcc superlattices with similar lattice constants, indicating that i-comp strands do not react with the i-motif structures under these conditions, and therefore the i-motif remains in the “contracted” state. In contrast, at pH 8 both classes of PAE superlattices underwent lattice constant expansion, but to different magnitudes. The ones with i-comp strands experienced an increase of 14 nm as opposed to 10 nm, a consequence of the increased rigidity due to double-strand formation (Figures 2A and S10). SAXS was used to follow these structural changes as a function of pH (Figure 2B,C). Note that for this sequence design, the pH trigger is expected to be around pH 6.5 based upon the literature.13 Interestingly, PAEs with i-comp strands exhibited the greatest change in lattice constants at more acidic conditions (pH 5.3−6.3; broad transition in Figure 2D) in comparison to those without i-comp strands where the shift occurred at more basic conditions (pH 6−6.3; sharp transition in Figure 2D). We hypothesize that the i-comp strands destabilize the i-motif linkers, and therefore the unfolding process is facilitated more at lower pH values compared with the system without i-comp strands. We believe that a broader transition is observed due to cooperative effects involving the DNA linkers on these PAEs. Multiple DNA bonding elements are present on the surface of each PAE, and increasing the B

DOI: 10.1021/jacs.8b02793 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society

blocks. These structures can be used to engineer well-defined colloidal crystals, and the i-motif linkers incorporated within them can be deliberately used to reconfigure the lattice structure on demand. Indeed, when one considers the vast number of structures now possible through colloidal crystal engineering with DNA, one should be able to extend this approach to more sophisticated architectures simply by utilizing nanoparticles with different sizes,4 shapes,22 and compositions,23 or by combining it with additional external inputs such as light and molecular signals.24 The ability to access such responsive crystalline structures will dramatically increase the scope of possibilities for researchers interested in exploring the stimuli-responsive optical, mechanical, and chemical properties of colloidal crystalline materials.25,26

length for a subportion of them likely triggers a small shift in interparticle distances. Note that the i-comp strands were only hybridized to i-motif linkers under neutral and basic conditions, indicating that pH, not i-comp strands, is the dominant factor in reconfiguring the i-motif structure (Figure S11). The role of the i-comp strands is primarily to add rigidity and increase the lattice constant further. By changing the location of the i-motif in the PAE, such that it is closer to the sticky end, the ability of the PAEs to assemble is controlled. For instance, when the i-motif was located near the outer shell of the PAE, the contracted state provided sufficient steric hindrance to prevent assembly at low pH. However, as the pH was increased, the i-motif unfolded and nanoparticle assembly ensued, allowing ordered superlattices to form upon annealing. This was confirmed both visually and via SAXS (Figure S12). Taking advantage of the ability to control the assembly of the PAEs through i-motifs, we designed a new class of PAEs consisting of a mixture of DNA strands with and without imotifs (Figure 3A). The strands without i-motifs were designed

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b02793. Methods (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Jinghan Zhu: 0000-0002-7248-3131 Chad A. Mirkin: 0000-0002-6634-7627 Present Address ∥

Wyss Institute, Harvard University, Boston, MA 02115

Author Contributions ⊥

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This material is based upon work supported by the following awards: Air Force Office of Scientific Research FA9550-17-10348 (DNA-functionalization of gold nanoparticles) and FA9550-16-1-0150 (oligonucleotide synthesis and purification); the Center for Bio-Inspired Energy Science (CBES), an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences DE-SC0000989 (nanoparticle superlattice assembly) and U.S. Army W911NF-15-1-0151 (melt measurements). This work made use of the IMSERC at Northwestern University, which has received support from the State of Illinois. SAXS measurements were carried out at the DuPont-NorthwesternDow Collaborative Access Team (DND-CAT) beamline located at Sector 5 of the Advanced Photon Source. DNDCAT is supported by E. I. Dupont de Nemours & Co., Dow Chemical Company, and the State of Illinois. S.W. acknowledges support from a PPG fellowship.

Figure 3. (A) Scheme showing an i-motif structure incorporated in the spacer region close to the sticky end, such that the binding ability of the PAEs is adjustable. PAEs were loaded with two different sets of linker strands: one with an i-motif (and a self-complementary sticky end), and the other without an i-motif (and a binary set of complementary sticky ends), such that the binding of each linker was activated only when prompted. (B) SAXS patterns confirmed two complete cycles of reversible change in crystal structure between fcc and bcc at pH 8 (green) and pH 5 (orange), respectively.

to have sticky ends complementary to a second set of particles, that also consisted of a mixture of normal and i-motif DNA strands. Therefore, when the i-motif strands are in the contracted state at pH 5, a bcc lattice forms. However, at pH 8, the expanded i-motifs are longer than the strands without imotifs and thus dominate binding. Here, the i-motif linker has a self-complementary sticky end, favoring fcc crystal assembly. As a result, by adjusting the bonding environment of the PAEs, the structure of the superlattices can be toggled between fcc and bcc, simply by selectively activating the different DNA strands (Figure 3A,B). Note that in the absence of the i-comp strands, even when the i-motifs were opened, a pure fcc phase crystal was not obtained, emphasizing the role the i-comp strands play in increasing rigidity and in this case bonding directionality (Figures S18 and S19). Again, SAXS was used to confirm reversibility through two complete cycles (Figure 3B). In summary, we synthesized and developed a new class of highly programmable, pH-responsive nanoparticle building

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DOI: 10.1021/jacs.8b02793 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX