This introductory lecture prefaces the 2024 New Horizons in Nanoelectrochemistry . A broad view of the previous Discussions related to nanoelectrochemistry is taken. Big ideas or concepts discussed at these previous meetings are identified, along with specific examples in each area. Closing comments aimed at a high level and related to where we are today and what is needed to continue to drive nanoelectrochemistry towards the horizon are considered.

Metal centers are essential for enzyme catalysis, stabilizing the active site, facilitating electron transfer, and maintaining the structure through coordination with amino acids. In this study, K238H-AeL nanopores with histidine sites were designed as single-molecule reactors for the measurement of single-molecule coordination reactions. The coordination mechanism of Au(III) with histidine and glutamate in biological nanopore confined space was explored. Specifically, Au(III) interacts with the nitrogen (N) atom in the histidine imidazole ring of the K238H-AeL nanopore and the oxygen (O) atom in glutamate to form a stable K238H-Au-Cl complex. The formation mechanism of this complex was further validated through single-molecule nanopore analysis, mass spectrometry, and molecular dynamics simulations. Introducing histidine and negative charge amino acids with carboxyl group into different positions within the nanopore revealed that the formation of the histidine-Au coordination bond in the confined space requires a suitable distance between the ligand and the central metal atom. By analyzing the association and dissociation rates of the single Au(III) ion under the applied voltages, it was found that a confined nanopore increased the bonding rate constant of Au(III)-histidine coordination reactions by around 10-100 times compared to that in the bulk solution and the optimal voltage for single-molecule. Therefore, nanopore techniques for tracking single-molecule reactions could offer valuable insights into designing metalloenzymes in metal-catalyzed organic reactions.

Automated synthesis planning has recently re-emerged as a research area at the intersection of chemistry and machine learning. Despite the appearance of steady progress, we argue that imperfect benchmarks and inconsistent comparisons mask systematic shortcomings of existing techniques, and unnecessarily hamper progress. To remedy this, we present a synthesis planning library with an extensive benchmarking framework, called SYNTHESEUS, which promotes best practice by default, enabling consistent meaningful evaluation of single-step and multi-step synthesis planning algorithms. We demonstrate the capabilities of SYNTHESEUS by re-evaluating several previous retrosynthesis algorithms, and find that the ranking of state-of-the-art models changes in controlled evaluation experiments. We end with guidance for future works in this area, and call on the community to engage in the discussion on how to improve benchmarks for synthesis planning.

The transition to a personalized point-of-care model in medicine will fundamentally change the way medicine is practiced, leading to better patient care. Electrochemical biosensors based on structure-switching aptamers can contribute to this medical revolution due to the feasibility and convenience of selecting aptamers for specific targets. Recent studies have reported that nanostructured electrodes can enhance the signals of aptamer-based biosensors. However, miniaturized systems and body fluid environments pose challenges such as signal-to-noise ratio reduction and biofouling. To address these issues, researchers have proposed various electrode coating materials, including zwitterionic materials, biocompatible polymers and hybrid membranes. Nafion, a commonly used ion exchange membrane, is known for its excellent permselectivity and anti-biofouling properties, making it a suitable choice for biosensor systems. However, the performance and mechanism of Nafion-coated aptamer-based biosensor systems have not been thoroughly studied. In this work, we present a Nafion-coated gold nanoporous electrode, which excludes Nafion from the nanoporous structures and allows the aptamers immobilized inside the nanopores to freely detect chosen targets. The nanopore electrode is formed by a sputtering and dealloying process, resulting in a pore size in tens of nanometers. The biosensor is optimized by adjusting the electrochemical measurement parameters, aptamer density, Nafion thickness and nanopore size. Furthermore, we propose an explanation for the unusual signaling behavior of the aptamers confined within the nanoporous structures. This work provides a generalizable platform to investigate membrane-coated aptamer-based biosensors.

Nanopores are emerging as a powerful tool for the analysis and characterization of nanoparticles at the single entity level. Here, we report that a PEG-based polymer electrolyte present inside the nanopore enables the enhanced detection of nanoparticles at low ionic strength. We develop a numerical model that recapitulates the electrical response of the glass nanopore system, revealing the response to be sensitive to the position of the polymer electrolyte interface. As proof of concept, we demonstrate the multimodal analysis of a nanoparticle sample by coupling the polymer electrolyte nanopore sensor with nanoimpact electrochemistry. This combination of techniques could deliver the multiparametric analysis of nanoparticle systems complementing electrochemical reactivity data provided by nanoimpact electrochemistry with information on size, shape and surface charge provided by nanopore measurements.

The kinetics of particle nucleation and growth are critical to a wide variety of electrochemical systems. While studies carried out at the single particle level are promising for improving our understanding of nucleation and growth processes, conventional analytical frameworks commonly employed in bulk studies may not be appropriate for single particle experiments. Here, we present scanning electrochemical cell microscopy (SECCM) studies of Ag nucleation and growth on carbon and indium tin oxide (ITO) electrodes. Statistical analyses of the data from these experiments reveal significant discrepancies with traditional, quasi-equilibrium kinetic models commonly employed in the analysis of particle nucleation in electrochemical systems. Time-dependent kinetic models are presented capable of appropriately analysing the data generated SECCM to extract meaningful chemical quantities such as surface energies and kinetic rate constants. These results demonstrate a powerful new approach to the analysis of single particle nucleation and growth data which could be leveraged in differentiating behavior within spatially heterogeneous systems.

This was the first to focus on the increasingly central role of big data, machine learning, and artificial intelligence in the chemical sciences. The aim was to critically discuss these topics, and to explore the question of how data can enable new discoveries in chemistry, both now and in the future. The programme spanned computational and experimental work, and encompassed emerging topics such as natural language processing, machine-learned potentials, optimization strategies, and robotics and self-driving laboratories. Here I provide some brief introductory comments on the history of this field, along with some personal views on the discussion topics covered, concluding with three future challenges for this area.

MoS is a promising electrocatalytic material for replacing noble metals. Nanoelectrochemistry studies, such as using nanoelectrochemical cell confinement, have particularly helped in demonstrating the preferential electrocatalytic activity of MoS edges. These findings have been accompanied by considerable research efforts to synthesize edge-abundant nanomaterials. However, to fully apprehend their electrocatalytic performance, at the single particle level, new instrumental developments are also needed. Here, we feature a highly sensitive refractive index based optical microscopy technique, namely interferometric scattering microscopy (iSCAT), for monitoring local electrochemistry at single MoS petal-like sub-microparticles. This work focuses on the oxygen reduction reaction (ORR), which operates at low current densities and thus requires high-sensitivity imaging techniques. By employing a precipitation reaction to reveal the ORR activity and utilizing the high spatial resolution and contrast of iSCAT, we achieve the sensitivity required to evaluate the ORR activity at single MoS particles.

Platinum-black (Pt-B) has been demonstrated to be an excellent electrocatalytic material for the electrochemical oxidation of hydrogen peroxide (HO). As Pt-B films can be deposited electrochemically, micro- and nano-sized conductive transducers can be modified with Pt-B. Here, we present the potential of Pt-B micro- and sub-micro-sized sensors for the detection and quantification of hydrogen (H) in solution. Using these microsensors, no sampling step for H determination is required and , in photocatalysis, the onset of H evolution can be monitored . We present Pt-B-based H micro- and sub-micro-sized sensors based on different electrochemical transducers such as microelectrodes and atomic force microscopy (AFM)-scanning electrochemical microscopy (SECM) probes, which enable local measurements , at heterogenized photocatalytically active samples. The microsensors are characterized in terms of limits of detection (LOD), which ranges from 4.0 μM to 30 μM depending on the size of the sensors and the experimental conditions such as type of electrolyte and pH. The sensors were tested for the H evolution by light-driven water-splitting, , using ascorbic acid or triethanolamine solutions, showing a wide linear concentration range, good reproducibility, and high sensitivity. Proof-of-principle experiments using Pt-B-modified cantilever-based sensors were performed using a model sample platinum substrate to map the electrochemical H evolution along with the topography using AFM-SECM.

We present here a glutamate oxidase (GluOx)-modified platinum (Pt) nanoelectrode with a planar geometry for glutamate detection. The Pt nanoelectrode was characterized using electrochemistry and scanning electron microscopy (SEM). The radius of the Pt nanoelectrode measured using SEM is ∼210 nm. GluOx-modified Pt nanoelectrodes were generated by dip coating GluOx on the Pt nanoelectrode in a solution of 0.9% (wt%) bovine serum albumin (BSA), 0.126% (wt%) glutaraldehyde, and 100 U mL GluOx. An increase in current was observed at +0.7 V Ag/AgCl/1 M KCl with adding increasing concentrations of glutamate. Two-sample -test results showed that there is a significant difference for current at +0.7 V between the blank and the added lowest glutamate concentration, as well as between adjacent glutamate concentrations, confirming that the increase in current is related to the increased glutamate concentration. The experimental current-concentration curve of glutamate detection fitted well to the theoretical Michaelis-Menten curve. At the low concentration range (50 μM to 200 μM), a linear relationship between the current and glutamate concentration was observed. The Michaelis-Menten constants of and were calculated to be 1.093 pA and 0.227 mM, respectively. Biosensor efficiency (the ratio of glutamate sensitivity to HO sensitivity) is calculated to be 57.9%. Enz (/HO sensitivity, an indicator of the amount of enzyme loaded on the electrode) of the GluOx-modified Pt nanoelectrode is 0.243 mM. We further compared the sensitivity of a GluOx-modified Pt nanoelectrode with a GluOx-modified carbon fiber microelectrode (7 μm diameter and a sensing length of ∼350 μm). Glutamate detection on the GluOx-modified carbon fiber microelectrode fitted well to a Michaelis-Menten like response. Based on the fitting, the GluOx-modified carbon fiber microelectrode exhibited an of 0.689 nA and a of 301.2 μM towards glutamate detection. The best linear range of glutamate detection on the GluOx-modified carbon fiber microelectrode is from 50 μM to 150 μM glutamate. The GluOx-modified carbon fiber microelectrode exhibited a higher potential requirement for glutamate detection compared to the GluOx-modified Pt nanoelectrode.

Single-entity electrochemistry (SEE) is an emerging field within electrochemistry focused on investigating individual entities such as nanoparticles, bacteria, cells, or single molecules. Accurate identification and analysis of SEE signals require effective data processing methods for unbiased and automated feature extraction. In this study, we apply and compare two approaches for step detection in SEE data: discrete wavelet transforms (DWT) and convolutional neural networks (CNN).

There has been a great amount of interest in nanopores as the basis for sensors and templates for preparation of biomimetic channels as well as model systems to understand transport properties at the nanoscale. The presence of surface charges on the pore walls has been shown to induce ion selectivity as well as enhance ionic conductance compared to uncharged pores. Here, using three-dimensional continuum modeling, we examine the role of the length of charged nanopores as well as applied voltage for controlling ion selectivity and ionic conductance of single nanopores and small nanopore arrays. First, we present conditions where the ion current and ion selectivity of nanopores with homogeneous surface charges remain unchanged, even if the pore length decreases by a factor of 6. This length-independent conductance is explained through the effect of ion concentration polarization (ICP), which modifies local ionic concentrations, not only at the pore entrances but also in the pore in a voltage-dependent manner. We describe how voltage controls the ion selectivity of nanopores with different lengths and present the conditions when charged nanopores conduct less current than uncharged pores of the same geometrical characteristics. The manuscript provides different measures of the extent of the depletion zone induced by ICP in single pores and nanopore arrays, including systems with ionic diodes. The modeling shown here will help design selective nanopores for a variety of applications where single nanopores and nanopore arrays are used.

Proteins play crucial roles in nearly all biological activities, with their functional structures deriving from stable folded conformations. Protein denaturation, induced by chemical and physical agents, is a complex process where proteins lose their stable structures, thereby impairing their biological functions. Characterizing protein denaturation at the single-molecule level remains a significant challenge. In this study, we developed non-adhesive silicon nitride nanonets coated with polyethylene glycol to capture individual proteins. We utilized these nanonets to investigate the denaturation of ovalbumin induced by guanidine hydrochloride (Gdn-HCl) and lead chloride. The entire denaturation and renaturation processes of a single ovalbumin molecule were monitored ionic current measurements through the nanonets. These non-sticky nanonets offer a versatile tool for real-time studies of structural changes during protein denaturation.

The recent developments in scanning electrochemical probe techniques focus on the strategy of scanning the electrolyte. For example, scanning electrochemical cell microscopy (SECCM) is based on holding the electrolyte in a glass capillary, while scanning gel electrochemical microscopy (SGECM) immobilizes the gel electrolyte on micro-disk electrodes or etched metal wires. In both SECCM and SGECM, the first and essential step is to bring the electrolyte probe into contact with the sample, which is very often achieved by current feedback with a constant applied potential between the probe and the sample. This work attempts to theoretically analyse the deformation of the electrolyte during this approaching process. For a liquid electrolyte in SECCM, surface tension is considered to counterbalance the gravity and electrostatic force in 2D cylindrical coordinates with axial symmetry. The deformation at equilibrium is solved under certain conditions. For a gel electrolyte, a viscoelastic gel is analysed with a simplified 1D geometry. Both equilibrium and dynamic approaching are considered. The results suggest that for both liquid and gel electrolytes, critical conditions exist for breaking the equilibrium. When the applied potential is higher or the distance is lower than the threshold, the force will not equilibrate and the electrolyte will deform until contact. The critical condition depends on the properties (surface tension for a liquid, elastic and viscous moduli for a gel) and geometry (radius of the capillary for a liquid, thickness for a gel) of the electrolyte. Prospects of further extending the work closer to real experimental scenarios, especially SGECM, are also discussed.

Ion transport through biological channels is influenced not only by the structural properties of the channels themselves but also by the composition of the phospholipid membrane, which acts as a scaffold for these nanochannels. Drawing inspiration from how lipid membrane composition modulates ion currents, as seen in the activation of the K channel in Streptomyces A (KcsA) by anionic lipids, we propose a biomimetic nanochannel system that integrates DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By modifying the length of the multibranched DNA nanowires generated through the hybridization chain reaction (HCR) and varying the concentration of the linker strands that integrate these DNA nanowire structures with the GO membrane, the composition of the membrane can be effectively adjusted, consequently impacting ion transport. This method provides a strategy for developing devices with highly efficient and tunable ion transport, suitable for applications in mass transport, environmental protection, biomimetic channels, and biosensors.

The next generation of electroactive materials will depend on advanced nanomaterials, such as nanoparticles (NPs), for improved function and reduced cost. As such, the development of structure-function relationships for these NPs has become a prime focus for researchers from many fields, including materials science, catalysis, energy storage, photovoltaics, environmental/biomedical sensing, The technique of scanning electrochemical cell microscopy (SECCM) has naturally positioned itself as a premier experimental methodology for the investigation of electroactive NPs, due to its unique capability to encapsulate individual, spatially distinct entities, and to apply a potential to (and measure the resulting current of) single-NPs. Over the course of conducting these single-NP investigations, a number of unexpected ( rarely-reported) results have been collected, including fluctuating current responses, and carrying of the NP by the SECCM probe, hypothesised to be due to insufficient NP-surface interaction. Additionally, locations with measurable electrochemical activity have been found to contain no associated NP, and conversely locations with no activity have been found to contain NPs. Through presenting and discussing these findings, this article seeks to highlight complications in single-NP SECCM experiments, particularly those arising from issues with sample preparation.

We have developed a new scanning probe approach for the delivery of a gas-phase reactant to the surface of an electrocatalyst through a self-replenishing bubble located at the end of a scanning probe. This approach enables local electrocatalytic rates to be detected under very-high mass transport rates due to the small distance between the gas-phase reactant in the bubble and the electrocatalyst surface. Here we report experiments for the delivery of carbon dioxide to a gold ultramicroelectrode surface using a micron-scale nanopipette. The approach curve profiles that we measure suggest a complex interplay between carbon dioxide reduction and hydrogen evolution which is mediated by both the probe-electrode distance and the potential of the gold ultramicroelectrode.

Local electrochemical impedance spectroscopy (LEIS) has emerged as a technique to characterize local electrochemical processes on heterogeneous surfaces. However, current LEIS heavily relies on lock-in amplifiers that have a poor gain effect for weak currents, limiting the achievements of high-spatial imaging. Herein, an integrated scanning electrochemical cell microscopy is developed by directly collecting the alternating current (AC) signal through a preamplifier. The recorded local current (sub nA-level) is compared with the initial excitation signal to get the parameters for Nyquist plotting. By integrating this method into scanning electrochemical cell microscopy (SECCM), an image of LEIS at the Indium Tin Oxide/gold (ITO/Au) electrode is obtained with a spatial resolution of 180 nm. The established SECCM platform is integrated such that it could be positioned into the limited space ( glove box) for real characterization of electrodes.

Plasma-activated Ringer's lactate solutions (PALs), which are Ringer's lactate solutions treated with non-thermal atmospheric-pressure plasma, have an anti-tumor effect and can be used for chemotherapy. As the anti-tumor effect of the PAL is influenced by the cell-treatment time, it is necessary to monitor the structural changes of the cell surface with non-invasive, nanoscale, and time-lapse imaging to understand the anti-tumor effect. In this study, to characterize the anti-tumor effect of the PAL, we used scanning ion conductance microscopy (SICM), using glass nanopipettes as probes, to visualize the structural changes of the cell surface. SICM time-lapse topographic imaging visualized a decrease in the movement of lamellipodia in normal cells and cancer cells after the PAL treatment. Furthermore, in normal cells, protrusive structures were observed on the cell surface. Time-lapse imaging using SICM allowed us to characterize the differences in the morphological changes between the normal and cancer cells upon exposure to the PAL.

We describe a single-molecule electrochemical imaging strategy to study the electrocatalytic (EC') mechanism. Using the fluorescent molecule ATTO647N at extremely low concentrations as the substrate, we confirmed its catalytic reduction to a nonfluorescent form in the presence of the mediator phenazine methosulfate (PMS) by imaging and counting fluorescent molecules. Conventional electrochemical current in cyclic voltammetry would not have allowed us to infer the existence of an EC' process or the PMS-mediated ATTO647N reduction. Additionally, we observed shifts in the catalytic reduction potential of ATTO647N at various mediator concentrations, which agree with the theoretical predictions by Savéant. Our work offers a new perspective on connecting single-molecule EC' behaviors with the conventional ensemble EC' mechanism, both practically and theoretically.

Scanning electrochemical cell microscopy (SECCM) is a powerful nanoscale electrochemical technique that advances our understanding of heterogeneity at the electrode-electrolyte interface. In SECCM, dual-channel nanopipettes can serve as the probe, and a voltage bias between the channels can control the local electrolyte environment inside the droplet cell migration and electroosmotic flow (EOF) between the channels, enabling applications including controlled electrodeposition of bimetallic nanoparticles with variable compositions. Herein, we show quantitatively how the voltage bias between the channels modulates the local electrolyte environment experiment and finite element modeling. Experimentally, redox molecules of different charges (, ferrocene derivatives and Ruthenium(III) hexamine) were filled in separate channels, where their limiting currents at the substrate electrode were used to distinguish the contribution of migration and EOF. Furthermore, EOF was visualized by fluorescence imaging. Finite element models were developed to further validate the experimental results quantitively. We showed that migration is affected by the charge number of the redox molecule. Meanwhile, EOF is affected by the surface charge on the wall of the nanopipette and the location of the slipping plane inside the electrical double layer, which can be tuned by the solution pH and the ionic strength of the electrolyte, respectively. The experimentally validated model can guide the precise modulation of droplet cell environment in SECCM, potentially enabling new scanning modes in SECCM.