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Recent advances in solid nano-pores/channel analysis Zi Long, Shenshan Zhan, Pengcheng Gao, Yongqian Wang, Xiaoding Lou, and Fan Xia Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04737 • Publication Date (Web): 21 Nov 2017 Downloaded from http://pubs.acs.org on November 25, 2017

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Analytical Chemistry

Recent advances in solid nano-pore/channel analysis Zi Long,1Φ Shenshan Zhan,2Φ Pengcheng Gao,1 Yongqian Wang,1 Xiaoding Lou1,2*and Fan Xia1,2* 1

Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, P. R. China 2 School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, P. R. China *Corresponding Authors: [email protected], [email protected] (Xiaoding Lou); [email protected], [email protected] (Fan Xia)

Contents Introduction ..................................................................................................................................... 1 Analysis Applications Based on Different Target-induced Structure ......................................... 3 Target-induced 0D Structure ................................................................................................. 3 Ions Small molecules Biological macromolecules Target-induced 1D Structure ................................................................................................. 7 Ions Small molecules Biological macromolecules Target-induced 3D Structure ............................................................................................... 11 Ions Small molecules Biological macromolecules Conclusion and Perspective.......................................................................................................... 16 Acknowledgments ......................................................................................................................... 18 References ...................................................................................................................................... 18

Introduction Various 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 (nano-pore/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 nano-pore/channel-based applications, the nano-pore/channel can be broadly sorted into two types, biological and solid state.17-21 Generally, the biological nano-pore/channel 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 nano-pore/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 including excellent durability and robustness, easy control over pores/channels geometry and surface properties, as well as good compatibilities with existing semiconductor and microfluidics fabrication techniques.39-43 Herein,

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main reports of analysis applications based on solid nano-pore/channel in recent 5 years (2013-2017) were reviewed, and focused on which an outlook was provided for future developments and directions in the field at the end. As 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” were stated separately and specifically depending on the biomimetic nanodevices those reports applied. Generally, the principle of analysis applications based on solid nano-pore/channel can be described as follows: molecules access in or attach on the inner surface of a nano-pore/channel, change the effective diameter of the nano-pore/channel, or affect the charge transfer as well as the wettability of the inner surface (or the confined space) of the nano-pore/channel, leading to ionic current changes that can be detected.46-48 Among these solid nano-pore/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 nano-pore/channel has been adopted usually.49-53 In these strategies, the captures/recognition elements specifically interact with their target analytes, forming “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 nano-pore/channel-based analysis applications are classified according to the dimensionality of the target-induced formed structure.

Scheme 1. Schematic illustration of target-induced 0D, 1D, 3D structure in the solid nano-pore/channel-based detection and analysis. (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 nano-pore/channel, just as if the target analyte is absorbed onto the inner surface, resulting “complex” which shows negligible size or dimensionality, it could be classified into nano-pore/channel analysis based on zero-dimensional (0D) structure. For example, a DNA linear probe, the molecular beacon (MB)54, the sandwich


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structure55 and quantum dots could be regarded as 0D structures.56 (2) Those analysis which could be ranked in the one-dimensional (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 reaction (HCR)59,60 are representative 1D structures. (3) Based on 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 is few report on detection and analysis which based on target-induced 2D structure in nano-pore/channel till 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 multi-directionally, of which the cross-linked DNA superstructures is a typical example.61-64

Analysis Applications Based on Different Target-induced Structure Target-induced 0D Structure As defined in the introduction part, in the target-induced 0D structure-based analysis applications, the target analytes interact with the captures/recognition elements directly. Thus the designing 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 so strong on some extent. Nevertheless, the strategies based on target-induced 0D structure still have emerged as an attractive, powerful platform, and been used for a wide range of analysis applications.65-68 Ions. In the applications of ion detection analysis, Wen and Bo et al. 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 “off” state once the chloride-responsive molecule modified. However, when Cl- passed through the nanochannel and bound to chloride-responsive 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 were present and the optimal concentration was 1 µM. In that situation, target Cl- interacted with the chloride-responsive molecule then induced 0D structure in solid nanochannels. Moreover, it’s worth noting that when Cl- were 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 nanochannels could switch between “on” and “off” states by adding and removing Cl- (Figure 1D).



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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. More recently, Wen and Bo et al. 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 track-etched 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, 2D, the current increased gradually with the increasing concentration, which exhibited high sensitivity. Besides, it does not influenced their activity in the presence of other alkali metal ions, which displayed excellent selectivity (Figure 2C, 2E). In another ionic transportation study, Tian and Jiang et al. prepared a bio-inspired 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. Another example, in 2014, Wen, Bo and Jiang et al. immobilized a fluoride-responsive functional molecule, 4-aminophenyl-boronic acid, onto a single conical PI nanochannel, developed a fluoride-driven


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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.

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 4-AB18C6-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. Small molecules. As for small molecules, In 2016, Zhai, Gao and co-workers et al. developed an artificial carbonic oxide (CO) regulated PET ion nanochannel by modifying the interior surface with ferroporphyrin through 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 3B, once bubbled CO, 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) that 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 et al. developed a conformation and charge co-modulated 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 excellent selectivity and good reversibility.74 In 2014, Li et al. reported an hour-glass shaped nanochannel based on cascade enzymatic catalysis and cation-selectivity for glucose monitoring. Combination of glucose oxidase and horseradish



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peroxidase, the nanochannel system displayed high catalytic efficiency and specificity towards glucose with the LOD of 15 µM. 75 In 2016, Ensinger et al. 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

Figure 3. (A) The scheme of the CO regulation ions transportation for 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 time, 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. Biological macromolecules. For biological macromolecules, it was worth noting that Li et al. designed L-cysteine (Cys) and D-Cys functionalized polyimide (PI) nanopores by introducing the Cys enantiomers onto the inner surface through a facile and high efficient photo-initiated “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 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 event counts for BSA transport in Cys enantiomers modified single nanopore over 10 s were shown in Figure 3F. From the picture they can draw 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 D-Cys nanopore, which further suggested that L-Cys


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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. Other biological macromolecules detection and analysis, such as Sun and Zhang et al. 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 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 et al. first developed a PET nanopore-based DNA-probe sequence-evolution, by successively designing six different DNA-probes to reveals characteristics of protein-DNA binding phenomena in a nanoscale confined space. Results shown that the core-hindrance and edge-hindrance contributed differently for the binding and the equilibrium between DNA-DNA hybridization and protein-DNA binding events mainly depended on their own free energy.15 In addition to the above mentioned applications of analysis for solid nanopores, there still have other strategies for solid nanopores analysis using 0D structure.79-83 For instance, based on a thiol-yne reaction strategy, Li et al. reported the Cys-responsive biomimetic PET single nanochannels and used it for sensing in urine samples, which exhibited good Cys selectivity and non-interference in human urine and complex matrices.84 More recently, Li et al. 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 beta-cyclodextrin, based on 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 relatively simple reaction, more complex reactions such as circular reaction or chain reaction are often involved in the 1D structure-based analysis, based on which considerable amount of researches have been carried out.16, 21 Ions. In 2016, Lou et al. displayed another dual-signal-output (fluorescence and ion current signal) amplification PET nanopore system that could can 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 “closed” state. In the meantime, fluorescence was dramatically amplified (fluorescence turned “on”) due to AIE effect. When S2- was added, the complexes were disassembled, then the next round for Hg2+ detection could be executed again. Sensitivity of the pre-modified 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



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modulated by Hg2+ and S2- has a good anti-interference property of other ions. What’s more, 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 and Xia et al. designed another PET nanopore for selectivity 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 et al. explored the influence of short and long polymer chains on the gating properties of 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 et al. presented a dual-signal-output (fluorescence and electric) PET nanochannel system by coordinating the fluorescence signal and the ionic current to uncover the In this study, gating process with an “onion-like” intermediate state.89 1,2-diphenylethene-1,2-diyl)bis(1,4-phenylene)-1,1’-diboronic acid that with AIE properties was chose to interact specifically with target glucose (Glu), which resulted in the formation of oligomers (Figure 4E). The formed oligomers effective reduced effective diameter of the nanochannels and blocked the transmembrane ionic current of them (open-to-close) along with the emission of the 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 response 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 examining 40 urine specimens and obtaining results that coincide with those given by standard assays used in hospitals.


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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. 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 and Xia et al. reported a highly efficient nanofluidic gating system



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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 transform 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 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 when the DNA assembly while it almost recovered back to its initial level after treat with ATP, leading to a smart and highly efficient nanofluidic gating system. Results shown 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 act as a whole (Figure 5D).

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 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. Biological macromolecules. Another progress have made by Xia and Guo et al. demonstrated an improved supersandwich structure within the PET nanopores that contained only one target


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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 of its long concatamers and provided a built-in signals 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 sub-nanomolar and such 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 towards 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).

Figure 6. (A) Supersandwich structure-based nanopore sensors for ATP and DNA detection; (B) The specificity of thus 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. Chemi. Int. Ed. 2013, 52, 2007-2011 (ref 96). Copyright 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Target-induced 3D Structure Compared with those 0D structure-based analysis, the 1D structure-based ones have amplified the ON-OFF ratio of the solid nano-pore/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 nano-pore/channel unoccupied, there is still room for improvement. What’s more, in the 0D/1D structure-based analysis, the radius of the solid nano-pore/channel has to be limited in small range, which could be extended to a larger range if 3D structure formed in the confined space. In view of these, many more ingenious design which would result in 3D structure were constructed, accompanied with which 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) self-assembly method (Figure 7A).97 N1-(2-(dimethyl(naphthalen-2-ylmethyl)ammonio)-ethyl)-N1,N1 -dimethylhexane-1,6-diaminium (NapDA)-modified PET nanochannel was designed and



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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)-3-oxo-spiro[isoindoline-1,9’-xanthen]-2-yl)-5-(1,2-dithiolan-3-yl)pent an-amide (Rhod-DPA). In the presence of Cu2+, the fluorescence was first activated then triggered configuration change of Rhod-DPA, which induced the plasmon resonance energy transfer from single AuNP to the transformed fluorescent molecules. The decreased scattering intensity of AuNPs confirms the translocation of nanoparticles. Just as some G-rich DNA molecules which can fold into G-quadruplex conformation99,100, some temperature-sensitive polymers can also be folded into three-dimensional conformations through shape changes. Gao and Lou et al. reported a “Plug and Play” PET channels 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, of which 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, this channels could response to three kinds of environment stimuli (temperature, pH and light) and present six kinds of responses cycling among four states.


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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. Small molecules. By applying linker DNA and Y-DNA units, Xia et al. successfully fabricated the cross-linked 3D DNA superstructures, and based on 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 cross-linked 3D structures once the pre-synthesized Y-DNA and linker were present. As the dihedral rotation between the two adjacent Y-DNAs was not the integral times of 180° but 1680.7°, the adjacent Y-DNAs cannot be placed in the same plane but extending 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 this 3D DNA superstructures compared with 0D and 1D DNA structures were 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).



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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. Biological macromolecules. Lou, Zhai and Xia et al. 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 (

channel analysis - Analytical

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