Carbon Nanomaterials and DNA: from Molecular Recognition to

Feb 23, 2016 - Applications. Hanjun Sun,. †,‡. Jinsong Ren, ... have been regarded as rising stars in many active research fields, such as electro...
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Carbon Nanomaterials and DNA: from Molecular Recognition to Applications Hanjun Sun,†,‡ Jinsong Ren,† and Xiaogang Qu*,† †

Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China ‡ Graduate School, University of Chinese Academy of Sciences, Beijing 100039, China CONSPECTUS: DNA is polymorphic. Increasing evidence has indicated that many biologically important processes are related to DNA’s conformational transition and assembly states. In particular, noncanonical DNA structures, such as the right-handed A-form, the left-handed Zform, the triplex, the G-quadruplex, the i-motif, and so forth, have been specific targets for the diagnosis and therapy of human diseases. Meanwhile, they have been widely used in the construction of smart DNA nanomaterials and nanoarchitectures. As rising stars in materials science, the family of carbon nanomaterials (CNMs), including two-dimensional graphene, onedimensional carbon nanotubes (CNTs), and zero-dimensional graphene or carbon quantum dots (GQDs or CQDs), interact with DNA and are able to regulate the conformational transitions of DNA. The interaction of DNA with CNMs not only opens new opportunities for specific molecular recognition, but it also expands the promising applications of CNMs from materials science to biotechnology and biomedicine. In this Account, we focus on our contributions to the field of interactions between CNMs and DNA in which we have explored their promising applications in nanodevices, sensing, materials synthesis, and biomedicine. For one-dimensional CNTs, twodimensional graphene, and zero-dimensional GQDs and CQDs, the basic principles, binding modes, and applications of the interactions between CNMs and DNA are reviewed. We aim to give prominence to the important status of CNMs in the field of molecular recognition for DNA. First, we summarized our discovery of the interactions between single-walled carbon nanotubes (SWNTs) with duplex, triplex, and human telomeric i-motif DNA and their interesting applications. For example, SWNTs are the first chemical agents that can selectively stabilize human telomeric i-motif DNA and induce its formation under physiological conditions. On the basis of this principle, two types of nanodevices were designed. One was used for highly sensitive detection of ppm levels of SWNTs in cells, and the other monitored i-motif DNA formation. Further studies indicated that SWNTs could inhibit telomerase activity in living cells and cause telomere dysfunction, providing new insight into the biological effects of SWNTs. Then, some applications that are based on the interactions between graphene and DNA are also summarized. Combined with other nanomaterials, such as metal and upconversion nanoparticles, several hybrid nanomaterials were successfully constructed, and a series of DNA logic gates were successfully developed. Afterwards, the newcomer of the carbon nanomaterials family, carbon quantum dots (CQDs), were found to be capable of modulating right-handed B-form DNA to lefthanded Z-form DNA. These were further used to design FRET logic gates that were based on the CQD-derived DNA conformational transition. Taking into account the remaining challenges and promising aspects, CNM-based DNA nanotechnology and its biomedical applications will attract more attention and produce new breakthroughs in the near future.

1. INTRODUCTION

After decades of development, the family of carbon nanomaterials (CNMs), including two-dimensional graphene, one-dimensional carbon nanotubes (CNTs), and zero-dimensional graphene or carbon quantum dots (GQDs or CQDs), have been regarded as rising stars in many active research fields, such as electronics, energy, imaging, sensing, and gene and drug delivery, based on their excellent physical and chemical properties.6−12 The interactions between DNA and CNMs have been the focus in this field. To date, the diverse interactions between CNMs and DNA of different structures, such as single-stranded, duplex, triplex, and quadruplex DNA, have been systematically studied, and their specific recognitions

DNA has several distinct conformations in vivo and encodes the genetic instructions for all known organisms.1 Among the different forms of DNA, the non-B form has received significant attention in recent years.1 This is because many studies have demonstrated that the non-B form of DNA is closely related to genetic instability, expansions, deletions, and DNA strand breaks and rearrangements, which consequently lead to human diseases.1 Moreover, DNA conformational transitions have been successfully used to construct smart nanodevices and nanoarchitectures.2−5 Therefore, the conformational transitions between the B-form and the non-B form of DNA are important not only for biology but also for biotechnology and materials science. © XXXX American Chemical Society

Received: November 20, 2015

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selectively induce human telomeric i-motif DNA formation under physiological conditions.21 The SWNT-COOH directly binds at the 5′-end major groove by interacting with C·C+ base pairs and the TAA loop of the i-motif sequence, thus changing the pKa of the C·C base pairs and resulting in the formation and stabilization of the i-motif structure (Figure 1A).21

provide new horizons for further applications in gene therapy, drug delivery, sensing, and nanotechnology. In this Account, we focus on our previous efforts to explore the interactions between CNMs and nucleic acids in addition to their applications in nanodevices, sensing, materials synthesis, and biomedicine. Following the developments in this field and the different dimensions of CNMs, we classify CNMs into three categories: CNTs, graphene, and CQDs or GQDs. The following discussions cover the basic principles, DNA binding modes, and applications of the interaction of CNMs with DNA. This Account offers important perspective on the future challenges and opportunities in this field.

2. CNTS AND DNA The one-dimensional materials among the CNMs, the CNTs, are well-ordered and hollow graphitic nanomaterials with high aspect ratios.6,7 According to their diameter (φ) and the number of graphene layers, CNTs can be divided into singlewalled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs).6,7 SWNTs are more often used to study their interactions with DNA than MWNTs.13 2.1. Interaction between CNTs and DNA

Both single-stranded (ssDNA) and double-stranded DNA (dsDNA) can adsorb onto SWNTs.14−26 ssDNA can helically wrap around a SWNT via π−π stacking interactions between the nucleotide bases and the SWNT sidewall.14,15 Generally, dsDNA has a weak interaction with SWNTs.26 Additionally, because dsDNA can interact with SWNTs via DNA’s major groove and DNA end adsorption,16,18−22 after a long-term interaction (six months), the adsorbed dsDNA can denature and wrap around the SWNTs by forming an ordered coating layer.23 The adsorbing DNA assists in the dispersion and separation of SWNTs,15 and the SWNTs protect the DNA from enzymatic cleavage.24,25 Furthermore, DNA molecules can also be covalently modified on the surface and end of CNTs.27−30 Our group has studied a series of DNA conformational transitions that are regulated by SWNTs.20,21,31−33 For duplex DNA, we found that SWNTs have different effects on poly[dGdC]:poly[dGdC] and poly[dAdT]:poly[dAdT] DNA. For GC-DNA, the DNA melting temperature (Tm) was decreased to 40 °C upon SWNT binding, but no Tm change occurred for AT-DNA. SWNTs induced a B-A transition for GC-DNA; however, AT-DNA resisted the transition. This is because the water activity is a driving force for the B to A transition, and the water activity (31) of the GC-rich region (81.2) is lower than in the AT-rich region (81.5). Thus, GCDNA undergoes the B to A transition more easily.20 Human telomeres consist of tandem repeats of the doublestranded DNA sequence of (5-TTAGGG):(5-CCCTAA). The G-rich strand (G-DNA) can form a G-quadruplex in which its complementary C-rich strand (C-DNA) may adopt a unique four-stranded i-motif structure with intercalated CC base pairs, which has been considered to be a specific anticancer target. The formation and biological function of this i-motif structure has attracted much attention. Several compounds have been reported to inhibit telomerase activity by stabilizing Gquadruplex DNA. However, only two molecules can stabilize both the G-quadruplex and the i-motif structure.21 A ligand that can selectively stabilize the i-motif DNA but not the Gquadruplex structure has not been reported. We found that carboxylated SWNTs can inhibit DNA duplex association and

Figure 1. (A) Human telomeric duplex equilibrium shifted by SWNTCOOH.21 Copyright 2006, National Academy of Sciences. (B) Schematic representation of the disproportionation of d(CT)·d(AG) and the condensation of control duplex DNA (CO-duplex) in the presence of SWNTs under physiological conditions. The control duplex cannot form triplex DNA.33 Copyright 2011, Oxford University Press.

Moreover, these interactions make SWNT-COOH effectively accelerate the cleavage rate of S1 nuclease,31 and they can accelerate the i-motif formation at pH 7.0 under cell-mimicking conditions, which suggests that SWNTs may modulate human telomeric DNA in vivo.32 Additionally, for unstable CGC+ triplex DNA, SWNTs can induce triplex formation via electrostatic interactions under physiological conditions to cause the disproportionation of d(CT)·d(AG) duplex into triplex d(C+T)·d(AG)·d(CT) and single-strand d(AG) (Figure 1B).33 2.2. Applications

The interactions between DNA and SWNTs have been the research focus in the field of CNT applications,14,17,19,25,29,30,34−41 and they have been used to construct nanodevices,29,30 sensing,34−38 material synthesis39,40 and for biomedical effects41 based on specific recognitions between SWNTs and DNA studied by our group. B

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self-assembly (Figure 2B).30 In contrast, by using other small molecules that could not induce triplex formation, the selfassembly of SWNTs did not occur.30 This small moleculedirected SWNT assembly offers the potential to screen gene therapy-based triplex-inducing agents and to construct desired SWNT multicomponent/multifunctional electronic architectures on the nanoscale.30 2.2.2. Sensors. With the large amount of production and many applications of CNTs, researchers have paid more attention to the biosafety and side effects of CNTs. Therefore, developing a low-cost, simple, and highly sensitive CNT detection assay is highly desirable.34 Inspired by SWNTs that are capable of inducing i-motif structure formation at physiological pH, a CNT electrochemical DNA (E-DNA) sensor was designed (Figure 3A).34 This E-DNA sensor was

2.2.1. Nanodevices and Nanoarchitectures. CNTs have been used in nano/microelectronic devices as excellent “building blocks”, resulting in a revolution in the electronics industry.29,30 One of the key challenges for the application of CNTs is how to assemble them into desired large architectures with more complex functions.29,30 Nucleic acids, which have a highly specific and precise capability of molecular recognition, offer many opportunities for fabrication of novel nanomaterials.2−5 Therefore, we developed two nanodevices that could induce and direct the self-assembly of SWNTs.29,30 The first nanodevice was via covalent ligation. Amino-modified C-DNAand G-DNA-attached SWNT-COOH was synthesized.29 Under acid conditions, the attached DNA formed i-motif and Gquadruplex structures, respectively, thus preventing SWNT aggregation.29 When the pH was increased to 7.0, the i-motif structure unfolded, and C-DNA hybridized with its complementary G-DNA to form a duplex, leading to the formation of a net-shaped SWNT assembly.29 The assembly and disassembly of SWNTs can be reversibly controlled via pH (Figure 2A).29 For the second nanodevice, we used a triplex formation inducer, coralyne, to disproportionate the SWNT-dT22·dA22 duplex into triplex dT22·dA22·dT22 and dA22, resulting in SWNT

Figure 3. (A) The i-motif DNA-based E-DNA sensor.34 Copyright 2009, American Chemical Society. (B) The DNA nanomachine to monitor the i-motif structure formation.35 Copyright 2009, Elsevier.

based on the conformational change of an electrode-bound, methylene blue-modified C-DNA.34 The SWNTs bound to CDNA kept the methylene blue away from the electrode surface and hindered electron transfer. Thus, this reduced the electrochemical signal.34 This E-DNA sensor sensitively detected SWNTs in the cell at a ppm level without using expensive instruments. More intriguingly, it distinguished SWNTs from MWNTs because the large-sized MWNTs cannot induce i-motif DNA formation.20,32 This design is suitable for auto, portable, and large-scaled analysis.34 Furthermore, the specific interactions between SWNTCOOH and C-DNA were also used to monitor i-motif structure formation (Figure 3B).35 Generally, detection of the i-motif structure is under acidic conditions. The monitoring of the i-motif formation is difficult under physiological conditions. Therefore, we developed the first SWNT-driven DNA nanomachine. In our design, a fluorescent dye-labeled G-rich DNA sequence was immobilized on a gold surface as the motor

Figure 2. (A) Schematic representation of the synthesis of DNASWNT conjugates and the self-assembly of the SWNT nanostructure, as directed by DNA hybridization.29 Copyright 2011, Wiley-VCH. (B) The SWNT-assembled nanostructure that is directed by coralyneinduced triplex formation and used for screening of triplex inducers.30 Copyright 2011, Oxford University Press. C

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Figure 4. Schematic representations of the detection assays for (A) S1 nucleases, (B) EcoRI endonucleases, and (C) EcoRI methylase.36 Copyright 2011, Wiley-VCH. (D) Schematic representations of the SNP detection of complementary and mismatched duplex DNA.37 Copyright 2010, WileyVCH. (E) Schematic representation of the Ag+ and Cys fluorescence detection mechanism using the SWNT−DNA system.38 Copyright 2010, Wiley-VCH.

DNA.35 The reversible hybridization between the motor DNA and its complementary C-DNA was modulated by SWNTsCOOH without changing the solution pH.35 This nanomachine removed the necessity of monitoring the i-motif structure formation under acidic conditions, thereby allowing the monitoring at physiological pH.35 Meanwhile, using the advantage of the different binding affinities of SWNTs with ssDNA and dsDNA, several different types of sensors were designed for disease diagnosis.36−38 Screening of nuclease activity is of great importance in clinical diagnostics and drug discovery.36 On the basis of the different degrees of SWNT assembly at high ionic strength, the nuclease activity was detected by monitoring the light scattering (LS) signal (Figure 4A−C).36 For S1 nuclease, it can cleave ssDNA into small fragments that cannot protect SWNTs effectively, resulting in low LS signals after centrifugation (Figure 4A).36 For EcoRI nuclease, a DNA sequence that can form a hairpin structure (HP-DNA) was designed as a substrate.36 The HPDNA could not wrap the sidewalls of the SWNTs, leading to low LS signals after centrifugation.36 EcoRI nuclease could cleave HP-DNA into ssDNA, resulting in a high LS signal (Figure 4B).36 Moreover, this sensor could be further used to detect the enzymatic activity of EcoRI methylase because of inhibition by EcoRI methylase of the cleavage of EcoRI nuclease (Figure 4C).36 This assay can be generally applied to detect any nuclease by using different DNA sequences as the substrate.36

Interestingly, we found that SWNTs themselves possess intrinsic peroxidase-like activity.37 A label-free enzymatic sensor37 (Figure 4D) was developed to detect diseaseassociated single nucleotide polymorphisms (SNPs). Because dsDNA-containing SNPs have a higher ability to protect the SWNTs from salt-induced aggregation,37 after centrifugation, the precipitate of the SWNTs on the bottom of the tube were redispersed in phosphate buffer.37 When TMB and H2O2 were added, the colorimetric signal of the obtained SWNTs (with dsDNA-containing SNPs) was remarkably higher than that of the complementary dsDNA. This simple design distinguishes highly sensitive single nucleotide-mutated SNPs in a human gene.37 Fluorescence techniques are powerful because of their high sensitivity, ease of operation, and online imaging.42 On the basis of these merits, a reusable fluorescent sensor was developed for the highly sensitive and selective detection of toxic Ag+ and cysteine (Cys) (Figure 4E).38 As a nanoquencher, SWNTs can almost completely quench the fluorescence of dye-labeled ssDNA by π−π stacking.38 However, in the presence of Ag+ and the semicomplementary ssDNA, a duplex is formed by means of C−Ag+ −C coordination chemistry, which increases the fluorescence and shows a high sensitivity and selectivity to Ag+.38 Additionally, because it is a strong Ag+ binding agent because of the formation of the Ag−S bond, Cys can remove Ag+ from C− Ag+−C base pairs. This leads to a decrease in the fluorescence D

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Accounts of Chemical Research signal again, thus producing a highly sensitive and selective detection method for Cys.38 2.2.3. Material Synthesis. Because CNTs can only emit weak infrared fluorescence, their applications are limited. In recent years, CNT hybrid materials have received significant attention.39,40,43 Using the lanthanide complex with its unique spectroscopic characteristics, such as its long luminescence lifetime, large Stoke’s shift, and sharp line-like atomic emission, we synthesized a novel luminescent Eu3+-complex-functionalized SWNT to overcome the autofluorescence and light scattering of most organic molecules.39 DNA further enhanced the red luminescence of this hybrid nanomaterial, and the enhancement depended on the DNA sequence and form (Figure 5A).39 Because DNA can wrap SWNTs and act as a

Figure 6. Schematic illustration of the telomerase inhibition and telomere uncapping that is induced by SWNT-COOH.41 Copyright 2012, Macmillan Publishers Limited.

which triggered a DNA damage response and caused cell senescence via upregulation of the p16 and p21 proteins.41 Our work provided new insights into understanding the biological importance of the i-motif structure and the biomedical effects of SWNTs.41

3. GRAPHENE AND DNA Graphene, especially chemically oxidized graphene, namely graphene oxide (GO), is most commonly used in biosensors, nanocarriers for drug and gene delivery, bioimaging, and cancer therapy because of its easy dispersion, scalable production, and ability to be readily manipulated. 8,10 Meanwhile, the interactions between GO and DNA have been extensively investigated.

Figure 5. (A) Synthetic route for the luminescent Eu3+-complex covalently modified SWNTs and its luminescence enhancement by DNA.39 Copyright 2010, American Chemical Society. (B) Schematic representation of the fabrication of SWNTs-DNA-AgNC nanohybrids.40 Copyright 2011, Wiley-VCH.

3.1. Interactions between Graphene and DNA

Generally, similar to CNTs, ssDNA binds stronger to graphene than dsDNA.44−46 The ssDNA can assist the dispersion and separation of GO sheets, and GO sheets can protect ssDNA from enzymatic cleavage.46 The binding affinity between GO sheets and ssDNA depends on the DNA sequence.47 The dsDNA can absorb onto GO sheets in high ionic strength solutions.48 Additionally, GO can bind to dsDNA at the major groove.49 In addition to the above noncovalent interaction modes, covalent ligation is another common method to modify graphene with DNA.50

template for preparing highly luminescent Ag clusters, another hybrid material was synthesized based on luminescent DNA− metal clusters.40 Two strands of DNA (1 and 2) were used to form a DNA−SWNT complex (Figure 5B).40 DNA-1 was used to effectively disperse the SWNTs, and DNA-2 was the template for synthesis of luminescent Ag clusters.40 The luminescent SWNT hybrids are useful for gene/drug delivery and biosensing in vivo.39,40 2.2.4. Biological Effects. SWNT-COOH can induce imotif structure formation under physiological conditions and accelerate i-motif formation under cell-mimicking conditions, which reveal the potential of SWNT-COOH as an anticancer agent. Therefore, we explored the biomedical effects of SWNTCOOH in cancer cells (Figure 6).41 Through the stabilization of the i-motif structure, SWNT-COOH inhibited telomerase activity.41 This resulted in uncapping the telomere and displacing the telomere-binding proteins from the telomere,

3.2. Applications

Compared with gold nanostructures and other carbon nanomaterials, GO has many advantages for biomedical applications, including hydrophilicity, long-term stability of suspension in water, and ease of postmodification. Recently, we used the advantages of the interactions between graphene and DNA and explored their applications for different fields.50−53 3.2.1. Nanodevice and Nanoarchitecture. Because DNA has specific molecular recognition properties and a variety of E

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Figure 7. (A) Left: an “OR” logic gate system with metallized DNA-1, cysteine as the input, and the fluorescent signal as the output. Right: an “INHIBIT” logic gate system with DNA-2, cysteine as the input, and the fluorescent signal as the output.51 Copyright 2011, Wiley-VCH. (B) Left: the ternary INH gate that is based on nucleic acids on the surface of UCNPs and FLSiNPs. Right: electronic equivalent circuitry and schematic truth table of the ternary INH gate.52 Copyright 2014, Wiley-VCH.

secondary structures, DNA has become an extremely useful tool for molecular computing.54 By using both GO−DNA and the thiol-metallized DNA interactions with Cys, several logic gates have been reported by using DNA as the input (Figure 7A).51 Although complementary, the fluorophore-labeled DNA (F-DNA) and the metallized DNA (M-DNA) could not form a duplex because metallization prevented their hybridization.51 However, upon adding GO sheets, the F-DNA adsorbed onto the GO sheets, resulting in quenching of the fluorescence.51 In the presence of Cys, Ag NPs were removed from the M-DNA by forming Ag−S bonds, resulting in the formation of a DNA duplex and recovering the fluorescence of F-DNA.51 Therefore, an OR gate and an INH gate were operated by using Cys and DNA as the inputs.51 Additionally, by using the thiol-blocking reagent, NEM, and Cys as the input, an INH gate was also constructed.51 This system could also be used for sensitive “turn-on” sensing of Cys.51

To produce more complex logic operations, we also regulated the multiple emissions of rare earth-containing upconversion NPs (UCNPs) for constructing multivalued logic gates52 (Figure 7B). ssDNA A modified with UCNPs adsorbed onto the GO sheet, resulting in the quenching of upconversion emissions via fluorescence resonance energy transfer (FRET).52 ssDNA C modified with fluorescent silica nanoparticles (FLSiNPs) could displace ssDNA B in duplex AB to form duplex AC, which put UCNPs and FLSiNPs in close proximity. The FRET occurred from UCNPs to FLSiNPs because of the overlap between the absorbance of the FLSiNPs and the green emission of the UCNPs.52 Conversely, the red emission of the FLSiNPs overlapped with the red emission of the UCNPs, increasing the red emission of the entire system.52 The weakened green emission and enhanced red emission of this system were observed at the same time.52 On the basis of these results, a ternary OR logic gate and a ternary INH gate were constructed by changing DNA sequences.52 F

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Accounts of Chemical Research 3.2.2. Material Synthesis

Graphene-based nanohybrids have been used in electronics, energy, imaging, sensing, and biomedicine because of their excellent properties that are derived from each constituent.9,10 Because ssDNA can disperse and separate GO sheets, we synthesized natural calf thymus DNA (ct-DNA)-modified graphene/Pd NP (DNA-graphene-Pd) hybrid materials and used them as supports for achieving higher catalytic activity (Figure 8).53 In this nanohybrid, ct-DNA not only assisted the

Figure 8. Schematic illustration of the design for DNA-graphene-Pd hybrid nanomaterials and their catalytic applications for the electrooxidation of formic acid and in the Suzuki reaction.53 Copyright 2012, American Chemical Society.

dispersion and separation of the graphene sheets but also assisted the anchoring of the Pd NPs on the sheets.53 The obtained DNA-graphene-Pd displayed a higher activity and durability in the electro-oxidation of formic acid than the commercial Pd/C catalyst, and it efficiently catalyzed the Suzuki reaction.53

4. CQDS AND GQDS WITH DNA Photoluminescent CQDs and GQDs are two types of zerodimensional materials in the family of CNMs.11,12 Unlike organic dyes and semiconductive QDs, CQDs and GQDs exhibit a higher resistance to photobleaching and blinking and have biocompatibility and low toxicity.11,12 Therefore, CQDs and GQDs have attracted significant attention in the fields of bioimaging, sensors, drug delivery, optoelectronic devices, and so forth.11,12 Several examples have been reported regarding the interactions between DNA and CQDs/GQDs.55−58

Figure 9. (A) Schematic representation of the B-Z DNA transition induced by SC-dots. (B) Scheme of the AND NAND logic gates principle. (C) Fluorescent spectra of (a) SC-dots only, (b) SC-dots/ ct-DNA, (c) SC-dots/ct-DNA/EB, and (d) SC-dots/EB. (D) Truth table of the AND and NAND gates and the (E) AND/NAND logic scheme. (F) Fluorescent spectra of (a) SC-dots/ct-DNA, (b) SCdots/ct-DNA/EB, (c) SC-dots/ct-DNA/NaI, and (d) SC-dots/ctDNA/EB/NaI. (G) Truth table of AND+INH/NAND+INH. (H) AND+INH/NAND+INH logic scheme.58 Copyright 2013, Oxford University Press.

4.1. Interactions between CQDs/GQDs and DNA 4.2. Applications

The DNA B-Z transition has received much attention since the discovery of Z-DNA.58 Our group reported that photoluminescent nitrogen-doped carbon dots that were prepared by D-(+)-glucose and spermine via microwave treatment (SCdots) can induce right-handed B-DNA to change to left-handed Z-DNA under physiological salt conditions. Additionally, SCdots induced the transition, demonstrating sequence and conformation selectivity (Figure 9A).58 The positively charged SC-dots bind to the major groove with GC preference, and the electrostatic interaction is important for inducing the B-Z transition by the SC-dots.58 Additionally, for larger-sized carbon NPs, they bind stronger to ssDNA than dsDNA, which is similar to the interaction of DNA with SWNTs and GO.56 As another zero-dimensional CNM, GQDs can intercalate into dsDNA at the major groove and bind much stronger than GO because of a size effect.55 Moreover, like SWNT-COOH, as reported by our group, carboxylated GQDs can also induce i-motif structure formation under alkaline or physiological conditions. This example further demonstrates that CNMs have specific DNA preferences.57

Inspired by SC-dots that are capable of inducing the DNA B-Z transition and FRET process between SC-dots and a DNA intercalator, EB, we developed several optical Z-DNA-based logic gates.58 As shown in Figure 9B−E, EB and ct-DNA worked as the inputs.58 Neither EB nor ct-DNA individually had much influence on the emission of the SC-dots.58 When both of the inputs were added, the SC-dots and EB could bind to ct-DNA simultaneously.58 Upon excitation at 400 nm, the emission of the SC-dots decreased, and the fluorescence of EB increased because an efficient FRET occurred from the SC-dots to EB.58 Thus, an AND gate and a NAND gate were constructed.58 When a third input was introduced, an iodide ion that could only quench the emission of the SC-dots upon binding to DNA, AND+NIH, and a NAND+NIH gates were designed (Figure 9F−H, respectively).58

5. CONCLUSIONS AND PERSPECTIVE In this Account, we focused on recent achievements of CNMsDNA, including their interaction mechanisms, working G

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Accounts of Chemical Research principles, and applications. DNA has a variety of conformations, and the DNA conformational transition is crucial for DNA to achieve its functions in vivo. Therefore, understanding how CNMs and DNA interact and their biological effects are fundamental and important. These effects will promote and direct the applications of CNMs-DNA in gene/drug delivery, sensors, material synthesis, nanodevices, and DNA nanotechnology. Although considerable progress has been made in this field, many unknown issues and challenges still exist. Future perspectives in this field may be summarized as follows: (1) With the rapid development of materials science, a variety of CNMs have been designed and explored in different biological and biomedical areas. Unfortunately, their interactions with DNA are still not fully understood. Significant effort should be devoted to unraveling their molecular interaction mechanisms, induced biological effects, and longterm biosafety. This will direct the proper methods to select and CNMs to use in different circumstances. (2) Rational designs of new types of CNMs that target specific DNAs still remain a great challenge. A solution to this problem may be offered by the rapidly growing field of surface science and DNA nanotechnology. Surface functionalization may be another method to achieve specific recognition between CNMs and DNA. (3) To date, although there have been some promising applications that have been designed based on the DNA conformation transition and the specific interactions between CNMs and DNA, few applications can be used in vivo. Many interactions between CNMs and DNA have been studied and visualized in vitro. We need to verify whether they can really work in vivo. Because CNMs have fascinating optical, magnetic, electronic, and mechanic properties, they can be developed as bioprobes to trace and monitor how they interact with their targets in vivo. This will result in many new findings and applications in the near future.

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at the Mississippi Medical Center and Nobel Laureate Professor Ahmed H. Zewail at the California Institute of Technology. Since late 2002, he has been a professor at the Changchun Institute of Applied Chemistry, CAS. From 12/2006 to 05/2007, he visited the group of Nobel Laureate Professor Alan J. Heeger at UCSB. His current research is focused on ligand−nucleic acids or related protein interactions and biofunctional materials for advanced medical technology.

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ACKNOWLEDGMENTS This work was supported by the 973 Project (2012CB720602, 2011CB936004) and NSFC (21210002, 21431007, and 21533008).

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AUTHOR INFORMATION

Corresponding Author

* Address correspondence to Xiaogang Qu. Fax: (+86) 43185262656 E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Hanjun Sun received his B.Sc. degree (2011) from Nanjing Normal University, China. He then joined to the Changchun Institute of Applied Chemistry as a Ph.D. candidate, majoring in Chemical Biology. His current scientific interest is focused on the fabrication of artificial enzyme- and nanocarbon-based biomaterials. Jinsong Ren received her B.Sc. degree at Nanjing University in 1990 and Ph.D. from Changchun Institute of Applied Chemistry, Chinese Academy of Sciences in 1995. From 1996 to 2002, she worked at the School of Medicine, UMMC and Department of Chemistry and Chemical Engineering, California Institute of Technology. In 2002, she took a position as a principal investigator at Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. Her current research is mainly focused on drug screening and DNA-based nanofunctional materials. Xiaogang Qu received his Ph.D. from the Chinese Academy of Sciences (CAS) in 1995 with the President’s Award of CAS. He moved to the USA afterwards and worked with Professor J. B. Chaires H

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DOI: 10.1021/acs.accounts.5b00515 Acc. Chem. Res. XXXX, XXX, XXX−XXX