Review Cite This: Anal. Chem. 2018, 90, 577−588
pubs.acs.org/ac
Recent Advances in Solid Nanopore/Channel Analysis Zi Long,†,∥ Shenshan Zhan,‡,∥ Pengcheng Gao,† Yongqian Wang,† Xiaoding Lou,*,†,‡ and Fan Xia*,†,‡ †
Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, Hubei 430074, P. R. China School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P. R. China
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CONTENTS
Analysis Applications Based on Different TargetInduced Structures Target-Induced 0D Structure Ions Small Molecules Biological Macromolecules Target-Induced 1D Structure Ions Small Molecules Biological Macromolecules Target-Induced 3D Structure Ions Small Molecules Biological Macromolecules Conclusion and Perspective Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments References
nanopore/channel in recent 5 years (2013−2017) were reviewed, and an outlook was provided for future developments and directions in the field. The “nanopore” is defined simply as a nanoscale pore having a depth less than its diameter, whereas “nanochannel” means the nanoscale diameter is much less than the pore depth;44,45 thus, in the following, “nanopore” or “nanochannel” was stated separately and specifically depending on the biomimetic nanodevices those reports applied. Generally, the principle of analysis applications based on solid nanopore/channel can be described as follows: molecules access or attach on the inner surface of a nanopore/channel, change the effective diameter of the nanopore/channel, or affect the charge transfer as well as the wettability of the inner surface (or the confined space) of the nanopore/channel, leading to ionic current changes that can be detected.46−48 Among this solid nanopore/channel-based detection and analysis, the strategy in which the capture/recognition element of the target analyte was functionalized or modified onto the inner surface of the nanopore/channel has usually been adopted.49−53 In these strategies, the captures/recognition elements specifically interact with their target analytes, forming a “complex” of different dimensionalities depending on the recognition mechanism and generating signal changes of different amplitude. Thus, in the following, after a clear definition on different dimensionalities was stated (Scheme 1), the recent advances of the solid nanopore/channel-based analysis applications are classified according to the dimensionality of the target-induced formed structure. (1) For the case in which almost all of the responsive target analyte reacted with the capture/recognition element near the inner surface of the nanopore/channel, just as if the target analyte is absorbed onto the inner surface, resulting in a “complex” which shows negligible size or dimensionality, it could be classified into nanopore/channel analysis based on zero-dimensional (0D) structure. For example, a DNA linear probe, the molecular beacon,54 the sandwich structure,55 and quantum dots could be regarded as 0D structures.56 (2) Those analyses which could be ranked in the onedimensional (1D) structure-based applications share one similarity, that is the formed structure composed by the capture and the target shows obvious and unidirectional growing length. The structures generated from supersandwich reaction57,58 or hybridization chain reaction59,60 are representative 1D structures.
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arious types of transmembrane pores and ion channels in the range of 1−100 nm are found in each biological cell,1−6 playing crucial roles in varieties of significant physiological activities such as maintaining cell osmotic balance and stabilizing cell volume.7−10 Inspired by this natural phenomenon, different biomimetic nanodevices (nanopore/ channel) with different characteristics have emerged as an attractive and powerful platform and have been used for a wide range of applications.11−16 As the key components of any nanopore/channel-based application, the nanopore/channel can be broadly sorted into two types, biological and solid state.17−21 Generally, the biological nanopores/channels are nanoscale holes embedded in electrically insulating membranes,22−27 while the solid state ones are tiny openings fabricated in thin inorganic or polymeric membranes.17,28−32 Both of these two types of nanopore/channel have the ability to confine the target analyte of interest in a nanoscale cavity,33−38 whereas compared with the biological type, the solid state type possesses the advantages of excellent durability and robustness and easy control over pores/channels geometry and surface properties, as well as good compatibilities with existing semiconductor and microfluidics fabrication techniques.39−43 Herein, the main reports of analysis applications based on solid © 2017 American Chemical Society
Special Issue: Fundamental and Applied Reviews in Analytical Chemistry 2018 Published: November 21, 2017 577
DOI: 10.1021/acs.analchem.7b04737 Anal. Chem. 2018, 90, 577−588
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ANALYSIS APPLICATIONS BASED ON DIFFERENT TARGET-INDUCED STRUCTURES Target-Induced 0D Structure. As defined in the introduction, in the target-induced 0D structure-based analysis applications, the target analytes interact with the captures/ recognition elements directly. Thus, the design of applications of this type seems relatively easy, of which the key part is to select or synthesize appropriate captures/recognition elements that can specifically recognize the targets. However, as the resulting “complex” reveals negligible dimensionality, the signal output would seem not as strong to some extent. Nevertheless, the strategies based on target-induced 0D structure still have emerged as an attractive, powerful platform and have been used for a wide range of analysis applications.65−68 Ions. In the applications of ion detection analysis, Wen, Bo, and co-workers developed a biomimetic voltage-gated chloride nanochannel by combining synthetic polyimide (PI) nanochannels with chloride-responsive molecules (Figure 1A).69 It was found that the nanochannel was in the “off” state once the chloride-responsive molecule was modified. However, when Cl− passed through the nanochannel and bound to chlorideresponsive molecules, the counterions were concentrated inside the nanochannels, increased the inner surface charge of the nanochannels, and enhanced the ionic conductivity, which caused the nanochannel to enter the “on” state (Figure 1B). Besides, as shown in Figure 1C, the modified nanochannel could be selectively activated by Cl− in spite of different concentrations of halogen being present, and the optimal concentration was 1 μM. In that situation, target Cl− interacted with the chloride-responsive molecule and then induced 0D structure in solid nanochannels. Moreover, it is worth noting that, when Cl− was released from the complex and transported to the other side of the nanochannels, it returned to the “off” state again. Thus, such biomimetic voltage-gated chloride
Scheme 1. Schematic Illustration of Target-Induced 0D, 1D, and 3D Structure in the Solid Nano-Pore/Channel-Based Detection and Analysis
(3) On the basis of the definition of 1D structure-based applications, it is easy to deduce that two-dimensional (2D) structure-based applications refer to the condition in which the resulted “complex” structure exhibits dimensionalities both in length and width. However, to the best of our knowledge, there are few reports on detection and analysis based on targetinduced 2D structure in nanopore/channel until now. Thus, the third classification of our Review is three-dimensional (3D) structure-based applications in which the “complex” structure shows distinct length and width and grows multidirectionally, of which the cross-linked DNA superstructure is a typical example.61−64
Figure 1. (A) Schematic showing the chloride-responsive PI nanochannels. (B) The sensitivity of the modified PI nanochannels to Cl−. (C) Cl− specific selectivity to different concentrations of F−, Br−, I−, and Cl−. (D) The illustration of cycling performance of the chloride activated PI nanochannel. Reprinted with permission from Liu, Q.; Wen, L.; Xiao, K.; Lu, H.; Zhang, Z.; Xie, G.; Kong, X. Y.; Bo, Z.; Jiang, L. Adv. Mater. 2016, 28, 3181−3186 (ref 69). Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. 578
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Figure 2. (A) Schematic demonstration of the Na+ and K+ activated ionic gates. (B) I−V characteristics of the 4-AB15C5-modified nanochannel before and after activation with different Na+ concentrations. (C) Selective activation of 4-AB15C5-modified with different alkali metal cations. (D) I−V characteristics of the 4-AB18C6-modified nanochannel before and after activation with different K+ concentrations. (E) Selective activation of 4AB18C6-modified with different alkali metal cations. Reproduced from Liu, Q.; Xiao, K.; Wen, L.; Lu, H.; Liu, Y.; Kong, X.-Y.; Xie, G.; Zhang, Z.; Bo, Z.; Jiang, L. J. Am. Chem. Soc. 2015, 137, 11976−11983 (ref 70). Copyright 2015 American Chemical Society.
Figure 3. (A) The scheme of the CO regulation ions transportation for the PET nanochannel. (B) Reversibility test of CO response by the addition and removal of CO. (C) The high selectivity toward CO in spite of the gas CO2 was present. Reprinted with permission from Xu, Y.; Sui, X.; Jiang, J.; Zhai, J.; Gao, L. Adv. Mater. 2016, 28, 10780−10785 (ref 73). Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) The scheme of cysteine-modified PI nanopores for BSA translocation. (E) The amount of BSA transported in naked nanopores and L/D-Cys immobilized nanopores at different times, which showed that BSA was preferentially transported through L-Cys modified nanopores. (F) The specific selectivity for BSA transportation. Reprinted with permission from Zhang, F.; Sun, Y.; Tian, D.; Li, H. Angew. Chem. 2017, 129, 7292−7296 (ref 77). Copyright 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
nanochannels could switch between “on” and “off” states by adding and removing Cl− (Figure 1D). More recently, Wen, Bo, and co-workers described the Na+ and K+ activated PI nanochannels for ion conduction by immobilizing 4′-aminobenzo-15-crown-5 (4-AB15C5) and 4′aminobenzo-18-crown-6 (4-AB18C6) onto the single ion tracketched conical nanochannels (Figure 2A).70 In their work, the Na+ and K+ activated ionic gates were able to open and close to control the ion conduction through the nanochannel because of the target-induced variations in effective pore size, wettability, and surface charge of the nanochannel. As shown in Figure 2B,D, the current increased gradually with the increasing concentration, which exhibited high sensitivity. Besides, it does not influence their activity in the presence of other alkali metal ions, which displayed excellent selectivity (Figure 2C,E). In
another ionic transportation study, Tian, Jiang, and co-workers prepared a bioinspired pH and potassium (K+) responsive double-gated polyethylene terephthalate (PET) nanosystem by immobilizing C-quadruplex (C4) and G-quadruplex (G4) DNA molecules onto the inner surface of the top and bottom tip side of a cigar-shaped nanochannel, respectively.71 In that nanosystem, the C4 DNAs kept the random single-stranded structures when pH = 7.5, and it formed into the four-stranded i-motif structures when pH = 4.5. Similarly, the G4 DNA molecules experienced K+-responsive conformational switches between random-coil single-stranded structures (in the absence of K+) and four-stranded tetraplex (G4) structures (in the presence of K+). Furthermore, this pH/K+-response nanosystem could be turned on and off simultaneously or alternately by using the DNA conformational conversions. In another 579
DOI: 10.1021/acs.analchem.7b04737 Anal. Chem. 2018, 90, 577−588
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Figure 4. (A) Schematic of the dual-signal-output PET nanopore system modulated by Hg2+and S2−. (B) The sensitivity of modified PET nanochannel for Hg2+ in different concentrations. (C) The current signal decrease ratios with different cations. (D) On/off ratio with different anions. Reproduced from Xu, X.; Hou, R.; Gao, P.; Miao, M.; Lou, X.; Liu, B.; Xia, F. Anal. Chem. 2016, 88, 2386−2391 (ref 87). Copyright 2016 American Chemical Society. (E) Schematic of PET nanochannel for detection of Glu. (F) The sensitivity of modified PET nanochannel for glucose in different concentrations. (G) the effects of transmembrane ionic current changes of the nanochannels on the interactions with different sugars. Reprinted with permission from Xu, X.; Zhao, W.; Gao, P.; Li, H.; Feng, G.; Zhao, Z.; Lou, X. NPG Asia Mater. 2016, 8, e234 (ref 89). Copyright 2016 Nature Publishing Group.
3B, once CO was bubbled, the nanosystem turned from an “off” state to an “on” state and the nanochannels revealed the cation selectivity, which preferred transporting cations and inhibited transporting anions. After adding methylene blue (MB), which was an antidote to CO poisoning, the I−V curve displayed linear characteristics and returned to the “off” state. Furthermore, ferroporphyrin-modified nanochannels exhibited high selectivity toward CO despite the presence of other gases, such as CO2 and N2 (Figure 3C), which showed excellent CO recognition capability. In a word, they used CO as the trigger for controlling the “on” and “off” states of the nanochannels through altering their inner surface charge and then got the signals. In 2016, Li and co-workers developed a conformation and charge comodulated ultrasensitive single glass conical nanopore to detect ATP with a low limit of detection (LOD) of 0.36 pM. This single glass-based nanosystem also displayed
example, in 2014, Wen, Bo, Jiang, and co-workers immobilized a fluoride-responsive functional molecule, 4-aminophenylboronic acid, onto a single conical PI nanochannel, developing a fluoride-driven ionic gate.72 This fluoride-driven ionic gate presented high sensitivity for F− and could actualize reversible switching between the “off” state and the “on” state by adding and removing F−. This type of fluoride-driven ionic gate may be widely used in many fields, including environmental monitoring and clinical medicine. Small Molecules. As for small molecules, in 2016, Zhai, Gao, and co-workers developed an artificial carbonic oxide (CO) regulated PET ion nanochannel by modifying the interior surface with ferroporphyrin through a one step coupling reaction (Figure 3A).73 In their work, they studied whether the CO response was reversible for the ferroporphyrin modified nanochannels by adding and removing CO. As shown in Figure 580
DOI: 10.1021/acs.analchem.7b04737 Anal. Chem. 2018, 90, 577−588
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excellent selectivity and good reversibility.74 In 2014, Li and coworkers reported an hourglass shaped nanochannel based on cascade enzymatic catalysis and cation-selectivity for glucose monitoring. When glucose oxidase and horseradish peroxidase were combined, the nanochannel system displayed high catalytic efficiency and specificity toward glucose with the LOD of 15 μM.75 In 2016, Ensinger and co-workers successfully employed the bovine serum albumin (BSA)modified single conical PET nanopore for enantioselectively recognizing L-tryptophan (L-Trp) over D-tryptophan (D-Trp) isomer, and the recognized concentration range was 0.1−1.5 mM.76 Biological Macromolecules. For biological macromolecules, it was worth noting that Li and co-workers designed L-cysteine (Cys) and D-Cys functionalized PI nanopores by introducing the Cys enantiomers onto the inner surface through a facile and highly efficient photoinitiated “thiol−yne” click reaction (Figure 3D).77 Then, they explored the protein transport properties by measuring the flux of BSA passing through L-Cys and D-Cys functionalized PI nanopores. The amount of BSA transported across the PI membranes as a function of time were demonstrated in Figure 3E. It was shown that the flux rate for protein transport in L-Cys immobilized nanopores was much higher than that in D-Cys-immobilized nanopores, which indicated the protein was preferentially transported through L-Cys immobilized nanopores. On the other hand, to gain further insight into the chiral selectivity that mediated the protein transport in biomimetic chiral nanopores, they prepared the single conical chiral nanopore for monitoring the individual translocation event through chem-clamp technology. The histogram of the event counts for BSA transport in Cys enantiomers modified single nanopore over 10 s was shown in Figure 3F. From the picture, they concluded that the event rate of BSA transport across the L-Cys nanopore was 12.9 events s−1 while it was only 1.6 events s−1 for the D-Cys nanopore, which further suggested that L-Cys immobilized nanopore accelerated BSA transport more strongly than D-Cys immobilized nanopore, and the chiral gate affected the protein transport. All the results showed that the protein was preferentially transported through L-Cys modified nanopores because of the chiral interaction which changes wettability of the nanopores’ inner surface. In another biological macromolecules detection and analysis, Sun, Zhang, and co-workers demonstrated a phosphorodiamidate morpholino oligos-functionalized PET nanochannel for label-free detection of microRNAs (miRNAs) with ultrasensitivity and high sequence specificity. In addition, this nanochannel-based biosensor attained a reliable LOD down to 1 fM in PBS and 10 fM in the serum sample, respectively.78 As most of the reports on the protein−DNA binding were carried out in an unconfined space that cannot be observed at the ensemble scale, Xia and co-workers first developed a PET nanopore-based DNA probe sequenceevolution, by successively designing six different DNA probes to reveals characteristics of protein−DNA binding phenomena in a nanoscale confined space. Results showed that the corehindrance and edge-hindrance contributed differently to the binding and the equilibrium between DNA−DNA hybridization and protein−DNA binding events mainly depending on their own free energy.15 In addition to the above-mentioned applications of analysis for solid nanopores, there still are other strategies for solid nanopores analysis using 0D structure.79−83 For instance, on the basis of a thiol-yne reaction strategy, Li and co-workers
reported the Cys-responsive biomimetic PET single nanochannels and used them for sensing in urine samples, which exhibited good Cys selectivity and noninterference in human urine and complex matrices.84 More recently, Li and co-workers developed a label-free PET nanochannel for enantioselective recognition of arginine by using BSA as the chiral selector.85 Another recent advance in chiral recognition based on solid nanopores was demonstrated by Wen, Jiang, and co-workers. Biomimetic PI single nanochannel was modified with βcyclodextrin, on the basis of which the chiral recognition of L-tryptophan was realized.86 Target-Induced 1D Structure. Different from the aforementioned target-induced 0D structure-based analysis which relies on a relatively simple reaction, more complex reactions such as a circular reaction or a chain reaction are often involved in the 1D structure-based analysis, on the basis of which a considerable amount of research has been carried out.16,21 Ions. In 2016, Lou and co-workers displayed a dual-signaloutput (fluorescence and ion current signal) amplification PET nanopore system that could be regulated by Hg2+ and S2− (Figure 4A).87 When aggregation-induced emission (AIE) molecules TPE-2T (1,1′-(((1,2-diphenylethene-1,2-diyl)bis(4,1-phenylene))bis(5-methylpyrimidine-2,4(1H,3H)dione))) reacted with Hg2+ to form long complexes onto the inner surface, the ion transportation nanochannel was blocked due to the decrease in its effective diameter; then, the current turned into a “closed” state. In the meantime, fluorescence was dramatically amplified (fluorescence turned “on”) due to the AIE effect. When S2− was added, the complexes were disassembled; then, the next round for Hg2+ detection could be executed again. Sensitivity of the premodified PET nanochannel for Hg2+ was investigated, as shown in Figure 4B; the values of current signal changes increased with the concentration of Hg2+, which presented a high sensitivity for Hg2+. Moreover, the 6-aminouracil-modified nanopores exhibited high selectivity to Hg2+ compared with other metal ions (Figure 4C) and S2− caused more significant changes in the current signal than other anions (Figure 4D). These results indicated that the nanopore system modulated by Hg2+ and S2− has a good anti-interference property of other ions. Furthermore, the successive calibration curves three times realized by subsequent reversible plug−unplug processes for the same nanopores enable great potential for the analysis or detection applications in living and bionic systems. In the same year, Lou, Xia, and co-workers designed another PET nanopore for selective detection of Zn2+ by utilizing a Zn2+-requiring DNAzymes and DNA supersandwich structure. In that system, the reliable selective LOD of Zn2+ was as low as 1 nM.16 Recently, Xia and co-workers explored the influence of short and long polymer chains on the gating properties of the anodic aluminum oxide (AAO) nanochannel.88 The macromolecular nanochannel was obtained by modifying the inner surface with poly(N-isopropylacrylamide-co-acrylamidophenylboronic acid) through the typical surface-initiated atom transfer radical polymerization. It was found that the macromolecular nanochannels polymerization for 60 min and polymerization for 10 min showed opposite gating behaviors, which were brought about by the different lengths of the same gating molecule and illustrated the importance of gating molecule length for sensitive nanochannels. Small Molecules. Lou and co-workers presented a dualsignal-output (fluorescence and electric) PET nanochannel 581
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Figure 5. (A) The highly efficient gating of alumina nanochannels by DNA supersandwich structure assemblies and ATP. (B) High gating efficiency was indicated by the distinct contrast in current−voltage responses of the functionalized nanochannels. (C) High gating efficiency in a series of nanochannels with different mean orifices in the range of 25−360 nm. (D) The changes in ionic conductance for the logic operations on eight parallel devices that were constructed on the same membrane. Reproduced from Jiang, Y.; Liu, N.; Guo, W.; Xia, F.; Jiang, L. J. Am. Chem. Soc. 2012, 134, 15395−15401 (ref 95). Copyright 2012 American Chemical Society.
Figure 6. (A) Supersandwich structure-based nanopore sensors for ATP and DNA detection. (B) The specificity of the functionalized PET nanopores for DNA detection. (C) Dose−response of the DNA sensor. (D) Selectivity of the ATP sensor against other types of NTPs. (E) Dose− response of the ATP sensor. Reproduced with permission. Reprinted with permission from Liu, N.; Jiang, Y.; Zhou, Y.; Xia, F.; Guo, W.; Jiang, L. Angew. Chem., Int. Ed. 2013, 52, 2007−2011 (ref 96). Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
fluorescence signal (off-to-on) due to the folding and aggregation of oligomers; thus, a dual-signal-output system was realized. Additionally, this modified nanochannel could respond to Glu with high sensitivity (Figure 4F), as well as show good specificity for glucose in the presence of xylose, arabinose, mannose, fructose, and galactose (Figure 4G). More importantly, the clinical test capability and practical application potential of this system have also been demonstrated by
system by coordinating the fluorescence signal and the ionic current to uncover the gating process with an “onion-like” intermediate state.89 In this study, 1,2-(diphenylethene-1,2diyl)bis(1,4-phenylene)-1,1′-diboronic acid with AIE properties was chosen to interact specifically with target glucose (Glu), which resulted in the formation of oligomers (Figure 4E). The formed oligomers effectively reduced the diameter of the nanochannels and blocked the transmembrane ionic current of them (open-to-close) along with the emission of the 582
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Figure 7. (A) Reversible and adjustable multiple gating states of the NapDA-modified single nanochannel through the LbL self-assembly into the channel. (B) The I−V curves of NapDA-modified nanochannel gated by different concentrations of CB[8]. (C) The ion current of the channel almost completely recovered by K+ after removing CB[8] molecules from the channel surface. (D) The reversibility between the complete blocking state-[10] and the primary NapDA-modified state. Reproduced from Fang, R.; Zhang, H.; Yang, L.; Wang, H.; Tian, Y.; Zhang, X.; Jiang, L. J. Am. Chem. Soc. 2016, 138, 16372−16379 (ref 97). Copyright 2016 American Chemical Society.
of its long concatamers and provided a built-in signal amplification. Furthermore, this reported sensor was based on self-assembly and disassembly of supramolecular DNA nanostructures in nanopores (two-way sensing) to turn off or turn on a smart nanofluidic switch through affecting the effective diameter of the nanopores. More interestingly, on the one hand, by coordinating such an improved structure into the nanopores, they designed a device to detect DNA of subnanomolar and such a nanofluidic sensing system possessed a high specificity for DNA (Figure 6B) with a reliable LOD of 10 fM (Figure 6C). On the other hand, an aptamer sequence for ATP has also been introduced into the capture and signal probes to detect ATP. As shown in Figure 6D, higher selectivity toward ATP than other nucleoside triphosphates (NTPs) was shown by this ATP aptamer-based sensing strategy, along with a dependable LOD of 1 nM (Figure 6E). Target-Induced 3D Structure. Compared with those 0D structure-based analyses, the 1D structure-based ones have amplified the ON−OFF ratio of the solid nanopore/channel to a great extent. Even so, as the target-induced 1D structures exhibit no dimensionality in width, which probably leave parts of the confined space of the solid nanopore/channel unoccupied, there is still room for improvement. Furthermore, in the 0D/1D structure-based analysis, the radius of the solid nanopore/channel has to be limited to a small range, which could be extended to a larger range if a 3D structure formed in the confined space. In view of this, many more ingenious designs, which would result in a 3D structure, were constructed, and preeminent performances were obtained. Ions. Zhang, Tian, Jiang, and co-workers reported the reversible and adjustable multiple gating nanofluidic diodes through a new supramolecular layer-by-layer (LbL) selfassembly method (Figure 7A). 9 7 N1-(2-(Dimethyl(naphthalen-2-ylmethyl)ammonio)-ethyl)-N1,N1-dimethylhex-
examining 40 urine specimens and obtaining results that coincide with those given by standard assays used in hospitals. Besides the above-mentioned signals amplification strategies, there are still many others that have been used in nanopores analysis or detection.74,88,90,91 Among which, the supersandwich structure, which could amplify the signal and improve the analysis sensitivity, is a good example.92−94 Notably, Guo, Xia, and co-workers reported a highly efficient nanofluidic gating system through inserting the supersandwich structures into alumina nanopores (Figure 5).95 It was found that, when the DNA supersandwich structures formed into the alumina nanochannels through self-assembling, it decreased the effective diameter of the nanochannels and caused the open-to-close state transformation of the them. However, the close-to-open process could be achieved by the disassembly of the supersandwich structures through DNA−ATP binding interactions (Figure 5A). In addition, as depicted in Figure 5B, only a very limited decrease in the transmembrane ionic current occurred after the alumina nanopores were modified by capture DNA. On the contrary, such ionic current remarkably fell down with the DNA assembly while it almost recovered back to its initial level after treatment with ATP, leading to a smart and highly efficient nanofluidic gating system. Results show that this device displayed a high ON−OFF ratio (up to 106) (Figure 5C) and fulfilled the IMPLICATION logic operations, in which multiple signal probes were assembled via multiple target DNAs, and then acted as a whole (Figure 5D). Biological Macromolecules. Another progress made by Xia, Guo, and co-workers demonstrated an improved supersandwich structure within the PET nanopores that contained only one target DNA, highly improving the detection limit (Figure 6A).96 In this study, a more complex DNA nanostructure was grafted onto the inner surface of the PET nanopores which contains multiple target-binding sites on each 583
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Figure 8. (A) Gating effect of the 3D superstructures built in solid nanopores. (B) Changes in the current−voltage responses before and after the DNA assembly and disassembly by ATP. (C) Comparison of the gating efficiency of three types of DNA structures. Reprinted with permission from Guo, W.; Hong, F.; Liu, N.; Huang, J.; Wang, B.; Duan, R.; Lou, X.; Xia, F. Adv. Mater. 2015, 27, 2090−2095 (ref 63). Copyright 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
fluorescent molecules. The decreased scattering intensity of AuNPs confirms the translocation of nanoparticles. Some Grich DNA molecules, which can fold into G-quadruplex conformation,99,100 and some temperature-sensitive polymers can be folded into three-dimensional conformations through shape changes. Gao, Lou, and co-workers reported a “Plug and Play” PET channel through a weak host−guest interaction between 3-amino-3-deoxy-α-cyclodextrin (α-CD) and azobenzene. The PET channel was modified with two kinds of responsive molecules: the poly(N-isopropylacrylamide) (PNIPAAm) responses to temperature and the poly-L-lysine (PLL) responses to pH.101 Due to a weak intermolecular interaction, the PNIPAAm and PLL molecules could coexist on the interior surface of PET channels. As a result, these channels could respond to three kinds of environmental stimuli (temperature, pH, and light) and present six kinds of responses cycling among four states. Small Molecules. By applying linker DNA and Y-DNA units, Xia and co-workers successfully fabricated the cross-linked 3D DNA superstructures, on the basis of which a highly efficient nanofluidic switch was developed (Figure 8A).63 In this study, the single-stranded capture DNA probes were first introduced onto the inner surface of the PET nanopore (the open state) and the tiles of Y-DNA could be further assembled into crosslinked 3D structures once the presynthesized Y-DNA and linker were present. The dihedral rotation between the two
ane-1,6-diaminium (NapDA)-modified PET nanochannel was designed and synthesized in this work, in which the naphthalene group on the inner surface of nanochannel could bind with cucurbit[8]uril (CB[8]) via π−π interaction to form monolayer or multilayers. Results indicated that the ion transport property of the NapDA-modified nanochannel was dependent on the concentration of CB[8] (Figure 7B−D). As these self-assemblies of different layer numbers possess prominent charge and steric effects, they can not only regulate the effective diameter, the surface charge density, and polarity, as well as the geometric asymmetry of the single nanochannel, but also enable the reversible gating of the single nanochannel among ion-conduction and multiple rectification states. This LbL supramolecular self-assembly strategy provided a facile avenue to enhance the functionalities of artificial nanochannels. Another recent advancement about nanopores analysis based on 3D has been demonstrated by Long and co-workers.98 Gold nanoparticle (AuNP)-based probe was used to investigate the single-nanoparticle translocation behavior through a silicon nitride solid nanopore. The AuNP probe was modified with a rhodamine derivative molecule, N-(3′,6′-bis(diethylamino)-3oxo-spiro[isoindoline-1,9′-xanthen]-2-yl)-5-(1,2-dithiolan-3yl)pentan-amide (Rhod-DPA). In the presence of Cu2+, the fluorescence was first activated and then triggered configuration change of Rhod-DPA, which induced the plasmon resonance energy transfer from single AuNP to the transformed 584
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Review
Figure 9. (A) The scattered Au 3D nanoparticles form distinct functional regions with an uncovered internal surface in confined AAO channels. (B) The Nyquist plots in EIS after hybridization (I−V curves insets). (C) The fractional comparisons of resistance (R) in I−V. Reprinted with permission from Gao, P.; Hu, L.; Liu, N.; Yang, Z.; Lou, X.; Zhai, T.; Li, H.; Xia, F. Adv. Mater. 2016, 28, 460−465 (ref 102). Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (D) The scheme of an electroosmotically driven nanopore-based device to detect MicroRNAs. (E) The LOD of miR-204. (F) The sequence-specific detection of miR-204. Reproduced from Zhang, Y.; Rana, A.; Stratton, Y.; Czyzyk-Krzeska, M. F.; Esfandiari, L. Anal. Chem. 2017, 89, 9201−9208 (ref 103). Copyright 2017 American Chemical Society.
the variations in DNA self-assembly and hybridization in the channels decorated by the “Janus” annulus on account of the ion permselectivity of AuNPs were revealed. By monitoring the current variations aroused from the surface charge changes of the “Janus” annulus-decorated channels, single nucleotide mutations in a linear DNA chain as well as terminal base polymorphisms were also detected with LODs of 10 × 10−9 M (Figure 9B,C). In 2017, Esfandiari and co-workers designed an electro osmotic flow (EOF) driven nanopore-based sensor which was integrated with γ-peptide nucleic acid (γ-PNA) probes conjugated beads to detect miR-204 and miR-210 (Figure 9D).103 In this system, EOF was induced as the driving force to transport PNA-beads harboring target miRs to the tip of the pore (sensing zone), which brought about pore blockades with unique and easily discriminable serrated shape electrical signals. Furthermore, it could specifically detect miR-204 and miR-210 extracted from different cell lines with low LODs of 1 and 10 fM, respectively (Figure 9E,F). By incorporating a lysozyme binding aptamer to a 5 nm AuNP carrier, Ivanov, Edel, and a co-worker demonstrated a nanopipette nanopore sensor to selectively detect lysozyme within the protein mixture.104 Remarkable selectivity to distinguish lysozyme from proteins with similar size and charge was also exhibited by this platform. As the possibility of
adjacent Y-DNAs was not in the integral times of 180° but instead 1680.7°; therefore, the adjacent Y-DNAs cannot be placed in the same plane but extend to 3D space, thus forming 3D DNA superstructures which decrease the effective diameter of the nanopore and block the nanopore for ionic conduction (the closed state). Nevertheless, the closed nanopores could be reopened as the cross-linked DNA superstructures were disassembled through the ATP−linker DNA interactions (the open state) (Figure 8B). Furthermore, the gating performance of these 3D DNA superstructures compared with 0D and 1D DNA structures was carried out. For 0D DNA structures, the length of DNA is too short versus the diameter of nanopores, exhibiting extremely low gating efficiency. The 1D DNA structures show excellent gating performance when the pore size ranged from 270 to 410 nm. In particular, 3D DNA superstructures display remarkable performance as a gatekeeper. Results showed that, when DNA was assembled into nanopores with diameters up to ca. 650 nm, a high ON−OFF gating ratio of 103−105 could be realized (Figure 8C). Biological Macromolecules. Lou, Zhai, Xia, and co-workers reported another solid nanopores analysis in 3D by scattering Au 3D nanoparticles to form characteristic functional regions with an uncovered internal surface in confined AAO channels (
