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This review highlights the important historical and technological developments of in situ ToF-SIEMS technique, especially, the challenges encountered when extending ToF-SIMS from a high vacuum condition to a liquid electrochemical environment.

Octameric Aep1 shows unique suitability for the gamma-cyclodextrin (γ-CD) adapter with 8 subunits, enabling the discrimination for β-nicotinamide mononucleotide.

Chirality is essential in nearly all biological organization and chemical reaction but is rarely considered due to technical limitations in identifying L/D isomerization. Using OmpF, a membrane channel from E. coli with an electrostatically asymmetric constriction zone, allows discriminating chiral amino acids in a single peptide. The heterogeneous distribution of charged residues in OmpF causes a strong asymmetric electrostatic field at the constriction. This asymmetry forces the sidechains of the peptides to specific orientations within OmpF, causing distinct ion current fluctuations. Using a statistical analysis of the respective ion current variations allows distinguishing the presence and position of each chiral amino acid. To explore potential applications, the disease-related peptide β-Amyloid, and its D-Asp1 isoform, as well as a mixture of the Icatibant peptide drug (HOE 140) and its D-Ser7 mutant, have been discriminated. Both chiral isomers were not applicable to be distinguished by mass spectrum approaches. These findings highlight a novel sensing mechanism for identifying single amino acids in single peptides and even for achieving single-molecule protein sequencing.

RNA modifications modulate essential cellular functions. However, it is challenging to quantitatively identify the differences in RNA modifications. To further improve the single-molecule sensing ability of nanopores, we propose a machine-learning algorithm called SmartImage for identifying and classifying nanopore electrochemical signals based on a combination of improved graph conversion methods and deep neural networks. SmartImage is effective for nearly all ranges of signal duration, which breaks the limitation of the current nanopore algorithm. The overall accuracy (OA) of our proposed recognition strategy exceeded 90% for identifying three types of RNAs. Prediction experiments show that the SmartImage owns the ability to recognize one modified RNA molecule from 1000 normal RNAs with OA90%. Thus our proposed model and algorithm hold the potential application in clinical applications.

Accurate discrimination of amyloid-β (Aβ) peptides containing familial point mutations would advance the knowledge of their roles in early-onset Alzheimer's disease. Herein, we simultaneously identified the mutant A21G, E22G, E22Q, and the wild-type (WT) Aβ

The transport of molecules and ions through biological nanopores is governed by interaction networks among restricted ions, transported molecules, and residue moieties at pore inner walls. However, identification of such weak ion fluctuations from only few tens of ions inside nanopore is hard to achieve owing to electrochemical measurement limitations. Here, we developed an advanced frequency method to achieve qualitative and spectral analysis of ion interaction networks inside a nanopore. The peak frequency fm reveals the dissociation rate between nanopore and ions; the peak amplitude am depicts the amount of combined ions with the nanopore after interaction equilibrium. A mathematical model for single-molecule frequency fingerprint achieved the prediction of interaction characteristics of mutant nanopores. This single-molecule frequency fingerprint is important for classification, characterization, and prediction of synergetic interaction networks inside nanoconfinement.

The potential distribution at the electrode interface is a core factor in electrochemistry, and it is usually treated by the classic Gouy-Chapman-Stern (G-C-S) model. Yet the G-C-S model is not applicable to nanosized particles collision electrochemistry as it describes steady-state electrode potential distribution. Additionally, the effect of single nanoparticles (NPs) on potential should not be neglected because the size of a NP is comparable to that of an electrode. Herein, a theoretical model termed as Metal-Solution-Metal Nanoparticle (M-S-MNP) is proposed to reveal the dynamic electrode potential distribution at the single-nanoparticle level. An explicit equation is provided to describe the size/distance-dependent potential distribution in single NPs stochastic collision electrochemistry, showing the potential distribution is influenced by the NPs. Agreement between experiments and simulations indicates the potential roles of the M-S-MNP model in understanding the charge transfer process at the nanoscale.

Proteins are responsible for the occurrence and treatment of many diseases, and therefore protein sequencing will revolutionize proteomics and clinical diagnostics. Biological nanopore approach has proved successful for single-molecule DNA sequencing, which resolves the identities of 4 natural deoxyribonucleotides based on the current blockages and duration times of their translocations across the nanopore confinement. However, open challenges still remain for biological nanopores to sequentially identify each amino acid (AA) of single proteins due to the inherent complexity of 20 proteinogenic AAs in charges, volumes, hydrophobicity and structures. Herein, we focus on recent exciting advances in biological nanopores for single-molecule protein sequencing (SMPS) from native protein unfolding, control of peptide translocation, AA identification to applications in disease detection.

The prompt introduction of single-molecule science into undergraduates’ curricula is an urgent but challenging task. However, the research experiments are often too complicated and the instruments are too expensive to be widely transferred into a compulsory course of undergraduate students. Herein, we introduce a recently developed nanopore technique into an accessible laboratory course for students with the advantages of simple operation, high repeatability, and low cost. The nanopore course serves to help undergraduates in practice to understand single-molecule behaviors, think at a single molecule level, and gradually develop single-molecule solutions for scientific issues. The learning activities for undergraduate students include setup of the instrument, fabrication of a biological nanopore on an artificial lipid bilayer membrane, detection of individual oligonucleotides, and data analysis. An experiment example is single-molecule detection of the model DNA sample poly(dA)n (n = 4, 5) using the aerolysin nanopore. As our developed nanopore sensing system is simple, portable, and easy to handle, the experiment course could be implemented and popularized in undergraduates’ laboratory education. For the undergraduate students who have taken general chemistry and/or biochemistry courses, this hands-on experience of nanopore experiments would benefit them with a better understanding of the chemical world at a single-molecule level and further using single-molecule tools in various applications including DNA and/or protein sequencing.

Measurements at the single-entity level provide more precise diagnosis and understanding of basic biological and chemical processes. Recent advances in the chemical measurement provide a means for ultra-sensitive analysis. Confining the single analyte and electrons near the sensing interface can greatly enhance the sensitivity and selectivity. In this review, we summarize the recent progress in single-entity electrochemistry of single molecules, single particles, single cells and even brain analysis. The benefits of confining these entities to a compatible size sensing interface are exemplified. Finally, the opportunities and challenges of single entity electrochemistry are addressed.

DNA lesions such as metholcytosine(mC), 8-OXO-guanine (OG), inosine (I), etc. could cause genetic diseases. Identification of the varieties of lesion bases are usually beyond the capability of conventional DNA sequencing which is mainly designed to discriminate four bases only. Therefore, lesion detection remains a challenge due to massive varieties and less distinguishable readouts for structural variations at the molecular level. Moreover, standard amplification and labeling hardly work in DNA lesion detection. Herein, we designed a single molecule interface from the mutant aerolysin (K238Q), whose sensing region shows high compatibility to capture and then directly convert a minor lesion into distinguishable electrochemical readouts. Compared with previous single molecule sensing interfaces, the temporal resolution of the K238Q aerolysin nanopore is enhanced by two orders, which has the best sensing performance in all reported aerolysin nanopores. In this work, the novel K238Q could discriminate directly at least three types of lesions (mC, OG, I) without labeling and quantify modification sites under the mixed heterocomposition conditions of the oligonucleotide. Such a nanopore electrochemistry approach could be further applied to diagnose genetic diseases at high sensitivity., Herein, we designed a single molecule interface from the mutant aerolysin (K238Q), whose sensing region shows high compatibility to capture and then directly convert a minor DnA lesion into distinguishable electrochemical readouts.

We have employed glass nanopore as a single molecule technique for direct sensing amyloidosis process of Aβ1–42 peptide, which of great significance in Alzheimer's disease., We have developed a glass nanopore based single molecule tool to investigate the dynamic oligomerization and aggregation process of Aβ1–42 peptides. The intrinsic differences in the molecular size and surface charge of amyloid aggregated states could be distinguished through single molecule induced characteristic current fluctuation. More importantly, our results reveal that the neurotoxic Aβ1–42 oligomer tends to adsorb onto the solid surface of nanopores, which may explain its instability and highly neurotoxic features.

The study of a single-molecule reaction under nanoconfinement is beneficial for understanding the reactive intermediates and reaction pathways. However, the kinetics model of the single-molecule reaction under confinement remains elusive. Herein we engineered an aerolysin nanopore reactor to elaborate the single-molecule reaction kinetics under nanoconfinement. By identifying the bond-forming and non-bond-forming events directly, a four-state kinetics model is proposed for the first time. Our results demonstrated that the single-molecule reaction kinetics inside a nanopore depends on the frequency of individual reactants captured and the fraction of effective collision inside the nanopore confined space. This insight will guide the design of confined nanopore reactors for resolving the single-molecule chemistry, and shed light on the mechanistic understanding of dynamic covalent chemistry inside confined systems such as supramolecular cages, coordination cages, and micelles.

Reading the primary sequence directly using nanopores remains challenging due to the complex building blocks of 20 proteinogenic amino acids and the corresponding sophisticated structures. Compared to the uniformly negatively charged polynucleotides, biological nanopores hardly provide effective ionic current responses to all heterogeneously charged peptides under nearly physiological pH conditions. Herein, we precisely design a N226Q/S228K mutant aerolysin which creates a new electrostatic constriction named R3 in-between two natural sensing regions for controlling the capture and translocation of heterogeneously charged peptides. At nearly physiological pH, the decoration of positive charges at this constriction gives a large velocity of electroosmotic flow (EOF), leading to a maximum 8-fold increase in frequency for the heterogeneously charged peptides with the net charge from +1 to -3. Even the duration time of the negatively charged peptide Aβ35-25D4 in N226Q/S228K AeL also rises from 0.07 ± 0.01 ms to 0.63 ± 0.01 ms after introducing the third electrostatic constriction. Therefore, the N226Q/S228K aerolysin nanopore with three electrostatic constrictions realizes the dual goals of both capturing and decelerating heterogeneously charged peptides without labelling, even for the folded peptides.

A fundamental question relating to protein folding/unfolding is the time evolution of the folding of a protein into its precisely defined native structure. The proper identification of transition conformations is essential for accurately describing the dynamic protein folding/unfolding pathways. Owing to the rapid transitions and sub-nm conformation differences involved, the acquisition of the transient conformations and dynamics of proteins is difficult due to limited instrumental resolution. Using the electrochemical confinement effect of a solid-state nanopore, we were able to snapshot the transient conformations and trace the multiple transition pathways of a single peptide inside a nanopore. By combining the results with a Markov chain model, this new single-molecule technique is applied to clarify the transition pathways of the β-hairpin peptide, which shows nonequilibrium fluctuations among several blockage current stages. This method enables the high-throughput investigation of transition pathways experimentally to access previously obscure peptide dynamics, which is significant for understanding the folding/unfolding mechanisms and misfolding of peptides or proteins., A solid-state nanopore based method is described for resolving protein-folding-related problems via snapshotting the folding intermediates and characterizing the kinetics of a single peptide.

The nanoparticle-based electrocatalysts' performance is directly related to their working conditions. In general, a number of nanoparticles are uncontrollably fixed on a millimetre-sized electrode for electrochemical measurements. However, it is hard to reveal the maximum electrocatalytic activity owing to the aggregation and detachment of nanoparticles on the electrode surface. To solve this problem, here, we take the hydrogen evolution reaction (HER) catalyzed by palladium nanoparticles (Pd NPs) as a model system to track the electrocatalytic activity of single Pd NPs by stochastic collision electrochemistry and ensemble electrochemistry, respectively. Compared with the nanoparticle fixed working condition, Pd NPs in the nanoparticle diffused working condition results in a 2-5 orders magnitude enhancement of electrocatalytic activity for HER at various bias potential. Stochastic collision electrochemistry with high temporal resolution gives further insights into the accurate study of NPs' electrocatalytic performance, enabling to dramatically enhance electrocatalytic efficiency.

The observation of single-particle surface-enhanced Raman scattering (SERS) has generated considerable interest both in the nanomaterials filed and in the single-particle spectroscopy community. It is a challenge to realize rapid, facile, and high throughput SERS at single nanoparticle level. Here, without the complex experimental device and difficult experimental operations, a general single-particle SERS technique has been achieved by using dark-field-assisted surface-enhanced Raman spectroscopy (DFSERS). This advanced method provides in-situ characterization of the chemical reaction performance at single gold nanorod.

Ensemble averaging measurements obscure the link between the electrochemical performance and the specific properties of an individual because of the interplay of inhomogeneity and heterogeneity. Nanocollision electrochemistry has attracted increasing interest because of its extremely high sensitivity, revealing the intrinsic properties of individual entities that are masked in the traditional ensemble measurements. In this perspective review, we summarized the recent developments in nanocollision-based single entity electrochemistry and photoelectrochemistry, the combined nanocollision electrochemistry with the other complementary techniques, as well as accurate data process. In closing, future challenges, opportunities, and destinations related to nanocollison electrochemistry were discussed.

Gold nanoparticles (AuNPs) have been demonstrated to serve as effective nanomaterial-based enzyme mimetics (nanozymes) for a number of enzymatic reactions under mild conditions. The intrinsic glucose oxidase and peroxidase activities of single AuNPs and Ag-Au nanohybrids, respectively, were investigated by single NP collision electrochemical measurements. A significantly high turnover number of nanozymes was obtained from individual catalytic events compared with the results from the classical, ensemble-averaged measurements. The unusual enhancement of catalytic activity of single nanozymes is believed to originate from the high accessible surface area of monodispersed NPs and the high activities of carbon-supported NPs during single-particle collision at a carbon ultramicroelectrode. This work introduces a new method for the precise characterization of the intrinsic catalytic activities of nanozymes, giving further insights to the design of high-efficiency nanomaterial catalysts.

The exploration of simultaneous removal of co-existing or multiple pollutants from water by the means of nanomaterials paves a new avenue that is free from secondary pollution and inexpensive. In the aquatic environment, river water contains a mixture of ions, which can influence the adsorption process. In this respect, removing heavy metal ions becomes a true challenge. Here, four heavy metal ions, namely, Pb2+, Cd2+, Cu2+, and Ni2+, have been successfully removed simultaneously from river water using ultrafine mesoporous magnetite (Fe3O4) nanoparticles (UFMNPs) based on the affinity of these metal ions toward the UFMNP surfaces as well as their unique mesoporous structure, promoting the easy adsorption. The individual removal efficiencies of Pb2+, Cd2+, Cu2+, and Ni2+ ions from river water were 98, 87, 90, and 78%, respectively, whereas the removal efficiencies of the mixed Pb2+, Cd2+, Cu2+, and Ni2+ ions were 86, 80, 84, and 54%, respectively, in the same river water. Thus, the data clearly indicate the complex removal of heavy metal ions in multi-ion systems. This study has demonstrated the huge potential of UFMNPs to be effective for their use in wastewater treatment, especially to simultaneously remove multiple heavy metal ions from aqueous media.

Our results indicated that a gold electrode participates in the redox reaction of [Fe(CN)6]3/4– by competing with it to form Au(CN)2–., Electrochemical redox conversion between ferricyanide and ferrocyanide on a gold electrode is one of the most classical reactions in electrochemistry. In textbooks, the gold electrode is seen as chemically inert, on which only the adsorption/desorption of [Fe(CN)6]3/4– and electron transfer take place. Here, the electrochemical process of [Fe(CN)6]3/4– on a gold electrode was revisited using a vacuum-compatible microfluidic electrochemical cell in combination with operando liquid ToF-SIMS. An intermediate, Au(CN)2–, was observed in the cyclic voltammetry of ferricyanide with an interesting periodic potential-dependent variation trend. It was demonstrated that the gold electrode participated in the redox reaction of [Fe(CN)6]3/4– by competing with it to form Au(CN)2–, since the formation constant was Fe(CN)63– > Au(CN)2– > Fe(CN)64–. The formation and evolution of Au(CN)2– depends on the ratio of Fe(iii) and Fe(ii) on the surface of the gold electrode, which was determined by the redox conversion between Fe(iii) and Fe(ii) as well as the electric field force-based attraction or repulsion between the gold electrode and [Fe(CN)6]3/4–. Both of these factors were potential-dependent, resulting in the periodic change of Au(CN)2– in the dynamic potential scan of [Fe(CN)6]3/4–. These results provided solid molecular evidence for the participation of the gold electrode in the [Fe(CN)6]3/4– redox system, which will deepen mechanistic understandings of related electrochemical applications.

Wild-type aerolysin (AeL) nanopores allow direct single nucleotide discrimination of very short oligonucleotides (≤10 nt) without labelling, which shows great potential for DNA sensing. To achieve real applications, one major obstacle of AeL is its poor capture ability of long single-stranded DNA (ssDNA, >10 nt). Here, we have proposed a novel and robust strategy for the electrostatic focusing of long ssDNA into a lithium-chloride (LiCl)-active AeL. By using this method, for the first time we have demonstrated AeL detection of ssDNA longer than 100 nt. Due to screening more negative charges, LiCl improves AeL capture ability of long ssDNA (i.e. 60 nt) by 2.63- to 10.23-fold compared to KCl. Further calculations and molecular dynamics simulations revealed that strong binding between Li+ and the negatively charged residue neutralized the AeL, leading to a reduction in the energy barrier for ssDNA capture. These findings facilitate the future high-throughput applications of AeL in genetic and epigenetic diagnostics.

Summary Muscle tissue performs crucial contraction/extension motions that generate mechanical force and work by consuming chemical energy. Inspired by this naturally created biomolecular machine, artificial molecular muscles are designed and synthesized to undertake linear actuation functions. However, most of these muscle-like actuators are performed at large ensembles, while to realize the nanoscale actuation at the single- to few-molecule level remains challenging. Herein, we developed an artificial muscle-like molecular actuator that can reversibly control the proximity of the attached nano-objects, gold nanoparticles, within the single-molecule length level by its stimuli-responsive muscle-like linear contraction/extension motion. The molecular actuation motion is accompanied by an optical signal output resulting from the plasmonic resonance properties of gold nanoparticles. Meanwhile, the thermal noise of the muscle-like molecular actuator can be overcome by integrating the optical signal over a sufficiently long period.

Correction for ‘An engineered third electrostatic constriction of aerolysin to manipulate heterogeneously charged peptide transport’ by Hongyan Niu et al., Chem. Sci., 2022, 13, 2456–2461, https://doi.org/10.1039/D1SC06459B.

Water clusters are ubiquitously formed in aqueous solutions by hydrogen bonding, which is quite sensitive to various environment factors such as temperature, pressure, electrolytes, and pH. Investigation of how the environment has impact on water structure is important for further understanding of the nature of water and the interactions between water and solutes. In this work, pH-dependent water structure changes were studied by monitoring the changes for the size distribution of protonated water clusters by in-situ liquid ToF-SIMS. In combination with a light illumination system, in-situ liquid ToF-SIMS was used to real-time measure the changes of a light-activated organic photoacid under different light illumination conditions. Thus, the proton transfer and pH-mediated water cluster changes were analyzed in real-time. It was found that higher concentration of free protons could lead to a strengthened local hydrogen bonding network as well as relatively larger protonated water clusters in both organic acid and inorganic acid. Besides, the accumulation of protons at the liquid-vacuum interface under light illumination was observed owing to the affinity of organic molecules to the low-pressure gas phase. The application of in-situ liquid ToF-SIMS analysis in combination with in-situ light illumination system opened up an avenue to real-time investigate light-activated reactions. Besides, the results regarding water structure changes in acidic solutions showed important insights in related atmospheric and physiochemical processes.

With the development of new instruments and methodologies, the highly dynamic behaviors of nanoparticle at the liquid-solid interface have been studied. However, the dynamic nature of the electrochemical behavior of individual nanoparticles on the electrode interface is still poorly understood. Here, we generalize scaling relations to predict nanoparticle-electrode interactions by examining the adsorption energy of nanoparticles at an ultramicroelectrode interface. Based on the theoretical predictions, we investigate the interaction-modulated dynamic electrochemical behaviors for the oxidation of individual Ag nanoparticles. Typically, significantly distinct current traces are observed owing to the adsorption-mediated motion of Ag nanoparticles. Inspired by restraining the stochastic paths of particles in the vicinity of the electrode interface to produce surface-confined current traces, we successfully realize high-resolution size measurements of Ag nanoparticles in mixed-sample systems. This work offers a better understanding of dynamic interactions of nanoparticles at the electrochemical interface and displays highly valuable applications of single-entity electrochemistry., Single-entity electrochemistry has been proposed for studying properties of single nanoparticles (NPs). Here, the authors make use of adsorption-mediated motion of Ag NPs to take individual NP size measurements using electrochemical impacts with excellent agreement to standard imaging techniques.

Aggregation-induced emission (AIE) as a unique photophysical process has been intensively explored for their features in fields from optical sensing, bioimaging to optoelectronic devices. However, all AIE luminogens (AIEgens) hardly recover into the initial dispersed state after illuminating at the ultimate aggregated state, which limits AIEgens to achieve reversible sensing and reproducible devices. To real-time manipulate the emission of AIEgen, here we take the advantage of confined space in the quartz nanopore to achieve a nanopore-size-dependent restriction of AIEgens for reversible conversions of “on-to-off” and “off-to-on” emission. By electrochemically manipulating 26 fL AIEgen solution inside nanopore confinement, AIE illuminates while moves along nanopore from the constricted tip to inside cavity at a velocity of 1.4–2.2 μm s−1, and vice versa. We further apply this dynamic manipulation for a target delivery of AIEgen into single cells, which opens up new possibility to design powerful and practical AIE applications., The difficulty in recovering the aggregation-induced emission fluorogens (AIEgens) to the initial dispersed state upon illuminating has limited their applications. Here, the authors employ the confined space in the quartz nanopore to achieve a nanopore-size dependent restriction of AIEgens.

Mimicking cellular transport mechanisms to make solid-state smart nanochannels has long been of great interest for their diverse applications, but it poses a critical synthetic challenge. Covalent organic frameworks (COFs) are porous crystalline materials with tailor-made nanochannels and hold great potential for ion and molecule transport. We demonstrate here for the first time that 2D COFs possess the necessary merits to be promising solid-state nanochannels for selective transport of amino acids, which are the basis for life. By imine condensations of a

Summary An aerolysin nanopore interface was introduced as a molecular machine to electrically read out the real-time photo-controlled motion of an azobenzene-geared DNA train with high spatial and temporal resolution. Under alternating UV and visible irradiation, each DNA train performed two regulated speeds of 1.9 and 6.3 bases/s corresponding to trans and cis states, respectively, with readily identified current signals. Each train type fell into the ultra-narrow current population with a full-width half maximum of 0.2–0.4 pA. The combination of a model molecular machine system and powerful aerolysin interface enabled the motions of every artificial molecular machine to be followed in real time.

Monitoring subtle changes in ionic current flow through a nanopore could be applied to observe single molecule reaction. Here, we introduced cysteine to substitute for lysine at position 238 constructing a mutant aerolysin K238C. It could be regarded as a nanoreactor to efficiently visualize chemical bonds making and breaking. The compound 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) was selected as a reactant coming into collisions on the interface of the pore to occur a reversible reaction. Our results showed that the mutant aerolysin could respond to three molecules of DTNB simultaneously and reflect corresponding levels with distinguishable current signals. Therefore, this method constitutes a simple, generic tool for monitoring single molecule reaction, which evokes a guidance for the mutant aerolysin towards the application of tracking other more reactions at single molecule level.

Quantifying the photoinduced electron transfer properties of a single entity is of paramount importance for clarifying the link between the photoelectrochemical performance and the specific properties of an individual. Here, we successfully monitored the photoelectrochemical behavior of a single dye-sensitized ZnO entity on a Au ultramicroelectrode with different TiO2 film thicknesses. Due to a trap-limited electron diffusion in TiO2 film, a sub-millisecond photocurrent transient was observed for an individual N719@ZnO associated with single-particle photocatalytic water splitting. Furthermore, a Monte Carlo random walk numerical simulation model was developed to simulate the photoinjected electron transport dynamics and recombination in a nanoparticulate TiO2 film. Our approach allowed the photocatalytic properties of N719 at the single-molecule level to be quantified, and electron diffusivity and electron collection efficiency as a function of the film thickness were estimated by simulation analyses. Ex...

An ultrasensitive photoelectrochemical method for achieving real-time detection of single nanoparticle collision events is presented. Using a micrometer-thick nanoparticulate TiO2-filmed Au ultra-microelectrode (TiO2@Au UME), a sub-millisecond photocurrent transient was observed for an individual N719-tagged TiO2 (N719@TiO2) nanoparticle and is due to the instantaneous collision process. Owing to a trap-limited electron diffusion process as the rate-limiting step, a random three-dimensional diffusion model was developed to simulate electron transport dynamics in TiO2 film. The combination of theoretical simulation and high-resolution photocurrent measurement allow electron-transfer information of a single N719@TiO2 nanoparticle to be quantified at single-molecule accuracy and the electron diffusivity and the electron-collection efficiency of TiO2@Au UME to be estimated. This method provides a test for studies of photoinduced electron transfer at the single-nanoparticle level.

Herein, green-fluorescent N-doped carbon quantum dots (N-CQDs) with quantum yield of 30.6% were prepared via a simple bottom-up electrochemical (EC) method using the mixtures of pyrocatechol and ethylenediamine as both precursors and electrolytes. The ON-OFF fluorescence (FL) principle that the FL intensity of the N-CQDs was quenched in the presence of Fe3+ was further extended to the ON-OFF-ON and ON-OFF-ON-OFF ones for pyrophosphate anions (PPi) and alkaline phosphatase (ALP) detection, respectively, based on the specific competitive interaction of N-CQDs with Fe3+ and PPi and the hydrolysis of PPi in the presence ALP. Under the optimized conditions, limit of detection (LOD) of 1.2 μM and 0.5 μM were achieved for assays of Fe3+ and PPi, respectively. Meanwhile, measurable evaluation of ALP activity was reached in a wide range from 5 to 360 U/L with a LOD of 1.1 U/L. The as-proposed sensors showed many advantages including label free, rapid, simple, low-cost, high sensitive, which has great promising application potential in vivo and in vitro clinical diagnosis and will promote the application of EC derived carbon nanomaterials.

The realization of the reversible inter-conversion between NADH and NAD+ is a long-term challenge in biological and energy-related chemistry. Here, we achieve the electrochemical reversible redox of NAD+/NADH derivatives by the functionalization of a gold electrode with a specially designed NAD+ derivative, and the electrochemical redox products are characterized by time-of-flight secondary ion mass spectrometry (ToF-SIMS).

Hydrogen generation based on photocatalytic water splitting is a promising strategy for renewable energy production. Significant efforts have been made to improve the photocatalytic efficiency. However, the light harvesting ability of photocatalytic systems in the visible region still needs to be significantly improved to enable them to be a competitive technology for hydrogen generation. Herein, for the first time, we synthesized 2D Zn–Ag–In–S (ZAIS) nanosheets with strong absorption in the visible region and applied them for photocatalytic hydrogen generation. The exploration of oxygen passivation (O-ZAIS) reduced the defect concentration and nonradiative decay. The hydrogen generation rate is up to 25.2 mmol g−1 h−1, which is 14.7 times higher than that of pristine ZAIS nanosheets. Furthermore, by introducing 2D Co3O4 as the co-catalyst, carrier separation is accelerated, giving rise to a hydrogen generation efficiency of 43.6 mmol g−1 h−1. To the best of our knowledge, this is the highest efficiency reported among all kinds of 2D photocatalysts.

A hybrid light/ToF-SIMS system was used to analyze the dynamic chemical changes of perovskite CH3NH3PbI3 films under light illumination, in order to reveal the mechanism of light instability for perovskite materials. Real-time material degradation and quasi-reversible iodine migration were successfully observed.

The size distribution and molecular structure of water clusters play a critical role in the chemical, biological and atmospheric process. The common experimental study of water clusters in aqueous solution is challenged due to the influence of local H-bonding environments on vibration spectroscopies or vacuum requirements for most mass spectrometry technologies. Here, the time-of-flight secondary ion mass spectrometry (ToF-SIMS) combining with a microfluidic chip has been applied to achieve the in-situ discrimination of the size distribution for water clusters in liquid water at room temperature. The results demonstrated that the presented method is highly system stable, reproducible and accurate. The comparison of heavy water with pure water was made to further demonstrate the accuracy of this technique. These results showed that (H2O)3H+ and (D2O)4D+ are the most dominant clusters in pure and heavy water, respectively. This one water molecule difference in the dominant cluster size may due to the nuclear quantum effects on water’s hydrogen bonded network. It is the first time to experimentally show the size distribution of water clusters over a wide range ( n =1–30) for pure (H2O) and heavy (D2O) water from molecular level. This technique provides an achievable method for liquid water, which offers a bridge to close the gap between theoretical and experimental study of water cluster in aqueous solution.

Clarifying the hidden but intrinsic feature of single nanoparticles by nanoelectrochemistry could help understand its potential for diverse applications. The uncontrolled interface and bandwidth limitation in the electrochemical measurement put the obstacle in single particle collision. Here, we demonstrate a well-defined 30 nm nanopore electrode with a rapid chemical-electrochemical fabrication method which provides a high reproducibility in both size and performance. A capacitance-based detection mechanism is demonstrated to achieve a high current resolution of 0.6 pA ±0.1 pA (RMS) and a high the temporal resolution of 0.01 ms. By utilizing this electrode, the dynamic interactions of every single particle in the mixture could be directly read during the collision process. The collision frequency is two orders of magnitude higher than previous reports, which helps reveal the hidden features of nanoparticles during the complex and multidimensional interaction processes.

In recent years, there has been growing demand for wearable chemosensors for their important potential applications in mobile and electronic healthcare, patient self‐assessment, human motion monitoring, and so on. Innovations in wearable chemosensors are revolutionizing the modern lifestyle, especially the involvement of both doctors and patients in the modern healthcare system. The facile interaction of wearable chemosensors with the human body makes them favorable and convenient tools for the detection and long‐term monitoring of the chemical, biological, and physical status of the human body at a low cost with high performance. In this Minireview, we give a brief overview of the recent advances and developments in the field of wearable chemosensors, summarize the basic types of wearable chemosensors, and discuss their main functions and fabrication methods. At the end of this paper, the future development direction of wearable chemosensors is prospected. With continued interest and attention to this field, new exciting progress is expected in the development of innovative wearable chemosensors.

Solid-state nanopore has been widely used for a variety of single-molecule analysis due to its advantage of size control, high stability, adjustable surface properties, and the potential of further integration. Therefore, the insensitive studies have applied for the nanopore analysis of DNA, RNA and proteins. In order to detect an oligonucleotide at single-molecule level, here, we fabricated two SiN X solid-state nanopores with diameter of 3.1 and 8.5 nm by controlled dielectric breakdown. The weak interaction between the solid-state nanopore and the oligonucleotide could be efficiently enhanced by electrochemical confined space effect of nanopore. We employed a 67-nt oligonucleotide as a model which could be electrochemically driven into a nanopore. The model ssDNA in nanopore with confined diameter of 3.1 nm could result in two kinds of electrochemical behaviors which assign to bumping and translocation. Our findings pave the path for a better understanding of the electrochemical behavior of the single molecule in a confined space.

Electrochemical analysis of single molecules is a method with the strong ability of the enhanced efficiency and ultra-sensitivity. Here, we demonstrate that the electrochemical confined space could efficiently convert single molecule characteristics into measurable electrochemical signatures with high temporal resolution. The human telomere repeat sequence T8 was used as a probe to determine the electrochemical confined effect in a nanopore. Our results show that the nanopore with comparable confined space of the telomere repeat sequence exhibits the most distinguishable single-molecule signals which suggest the folded conformation of T8. This method will greatly extend the lifetime of a metastable conformation for a single biomolecule by strong analyte-nanopore interactions, which brings the new insight into the understanding of the biomolecule’s function at single-molecule level.

The monitoring of cancer biomarkers is crucial to the early detection of cancer. However, a limiting factor in biomarker analysis is the ability to obtain the multilayered information of various biomarker molecules located at different parts of cells from the plasma membrane to the cytoplasm. A two-stage dissociation nanoparticle system based on multifunctionalized polydopamine-coated gold nanoparticles (Au@PDA NPs) is reported, which allows for the two-stage imaging of cancer biomarkers in single cells. We demonstrate the feasibility of this strategy on sialic acids (SAs), p53 protein, and microRNA-21 (miRNA-21) in MCF-7 breast cancer cells by two custom-built probes. Furthermore, the multicolor fluorescence information extracted is used for the monitoring of biomarker expression changes under different drug combinations, which allows us to investigate the complex interactions between various cancer biomarkers and to describe the cancer biomarker-synergic networks in single cells.

In this perspective, we discuss the challenges, advances and opportunities in electroanalytical chemistry at nanoelectrodes, including nanoelectrode fabrication, real-time characterizations, and high-performance electrochemical instrumentation., Nanoelectrodes, with dimensions below 100 nm, have the advantages of high sensitivity and high spatial resolution. These electrodes have attracted increasing attention in various fields such as single cell analysis, single-molecule detection, single particle characterization and high-resolution imaging. The rapid growth of novel nanoelectrodes and nanoelectrochemical methods brings enormous new opportunities in the field. In this perspective, we discuss the challenges, advances, and opportunities for nanoelectrode fabrication, real-time characterizations and high-performance electrochemical instrumentation.