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Label-free single-molecule detection has been achieved so far by funnelling a large number of ligands into a sequence of single-binding events with few recognition elements host on nanometric transducers. Such approaches are inherently unable to sense a cue in a bulk milieu. Conceptualizing cells’ ability to sense at the physical limit by means of highly-packed recognition elements, a millimetric sized field-effect-transistor is used to detect a single molecule. To this end, the gate is bio-functionalized with a self-assembled-monolayer of 10 12 capturing anti-Immunoglobulin-G and is endowed with a hydrogen-bonding network enabling cooperative interactions. The selective and label-free single molecule IgG detection is strikingly demonstrated in diluted saliva while 15 IgGs are assayed in whole serum. The suggested sensing mechanism, triggered by the affinity binding event, involves a work-function change that is assumed to propagate in the gating-field through the electrostatic hydrogen-bonding network. The proposed immunoassay platform is general and can revolutionize the current approach to protein detection. The sensing capability of nanometric transducers designed for label-free single molecule detection has been limited by the small number of recognition elements. Here, the authors demonstrate a millimetre-sized field effect transistor capable of selective single-molecule Immunoglobulin-G detection.

Single-molecule sensing is becoming a major driver in biomarker assays as it is foreseen to enable precision medicine to enter into everyday clinical practice. However, among the single-molecule detection methods proposed so far, only a few are fully exploitable for the ultrasensitive label-free assay of biofluids. Firstly introduced single-molecule sensing platforms encompass low-background-noise fluorescent microscopy as well as plasmonic and electrical nanotransducers; these are generally able to sense at the nanomolar concentration level or higher. Label-based single-molecule technologies relying on optical transduction and microbeads that can scavenge and detect a few biomarkers in the bulk of real biofluids, reaching ultralow detection limits, have been recently commercialized. These assays, thanks to the extremely high sensitivity and convenient handling, are new trends in the field as they are paving the way to a revolution in early diagnostics. Very recently, another new trend is the label-free, organic bioelectronic electrolyte-gated large transistors that can potentially be produced by means of large-area low-cost technologies and have been proven capable to detect a protein at the physical limit in real bovine serum. This article offers a bird’s-eye view on some of the more significant single-molecule bioanalytical technologies and highlights their sensing principles and figures-of-merit such as limit of detection, need for a labelling step, and possibility to operate, also as an array, directly in real biofluids. We also discuss the new trend towards single-molecule proof-of-principle extremely sensitive technologies that can detect a protein at the zeptomolar concentration level involving label-free devices that potentially offer low-cost production and easy scalability.

Electrolyte-gated transistors (EGTs), capable of transducing biological and biochemical inputs into amplified electronic signals and stably operating in aqueous environments, have emerged as fundamental building blocks in bioelectronics. In this Primer, the different EGT architectures are described with the fundamental mechanisms underpinning their functional operation, providing insight into key experiments including necessary data analysis and validation. Several organic and inorganic materials used in the EGT structures and the different fabrication approaches for an optimal experimental design are presented and compared. The functional bio-layers and/or biosystems integrated into or interfaced to EGTs, including self-organization and self-assembly strategies, are reviewed. Relevant and promising applications are discussed, including two-dimensional and three-dimensional cell monitoring, ultra-sensitive biosensors, electrophysiology, synaptic and neuromorphic bio-interfaces, prosthetics and robotics. Advantages, limitations and possible optimizations are also surveyed. Finally, current issues and future directions for further developments and applications are discussed.Electrolyte-gated transistors (EGTs) are fundamental building blocks of bioelectronics, which transduce biological inputs to electrical signals. This Primer examines the different architectures of EGTs, their mechanism of operation and practical considerations related to their wide range of applications.

Early diagnosis of the infection caused by human immunodeficiency virus type-1 (HIV-1) is vital to achieve efficient therapeutic treatment and limit the disease spreading when the viremia is at its highest level. To this end, a point-of-care HIV-1 detection carried out with label-free, low-cost, and ultra-sensitive screening technologies would be of great relevance. Herein, a label-free single molecule detection of HIV-1 p24 capsid protein with a large (wide-field) single-molecule transistor (SiMoT) sensor is proposed. The system is based on an electrolyte-gated field-effect transistor whose gate is bio-functionalized with the antibody against the HIV-1 p24 capsid protein. The device exhibits a limit of detection of a single protein and a limit of quantification in the 10 molecule range. This study paves the way for a low-cost technology that can quantify, with single-molecule precision, the transition of a biological organism from being “healthy” to being “diseased” by tracking a target biomarker. This can open to the possibility of performing the earliest possible diagnosis.

Alzheimer’s disease (AD) causes a great socioeconomic burden because of its increasing prevalence and the lack of effective therapies. The multifactorial nature of AD prompts researchers to search for new strategies for discovering disease-modifying therapeutics. To this extent, the multitarget approach holds the potential of synergic or cooperative activities arising from compounds that are properly designed to address two or more pathogenetic mechanisms. As a privileged and nature-friendly scaffold, coumarin has successfully been enrolled as the heterocyclic core in the design of multipotent anti-Alzheimer’s agents. Herein, we comprehensively summarize the most recent literature (2018–2023), covering the rational design and the discovery of coumarin-containing multitarget directed ligands (MTDLs) whose anti-AD profile encompassed at least two different biological activities relevant for disease onset and progression. To enhance the clarity of presentation, synthetic coumarin-based MTDLs are categorized into four clusters based on their substitution pattern and reported bioactivities: (i) mono-, (ii) di-, and (iii) polysubstituted coumarins directed at protein targets, and (iv) coumarins directed at protein targets with additional metal-chelating features. Before discussing multimodal coumarins, the rationale for addressing each biological target is briefly presented.

The continuous improvement of the technical potential of bioelectronic devices for biosensing applications will provide clinicians with a reliable tool for biomarker quantification down to the single molecule. Eventually, physicians will be able to identify the very moment at which the illness state begins, with a terrific impact on the quality of life along with a reduction of health care expenses. However, in clinical practice, to gather enough information to formulate a diagnosis, multiple biomarkers are normally quantified from the same biological sample simultaneously. Therefore, it is critically important to translate lab-based bioelectronic devices based on electrolyte gated thin-film transistor technology into a cost-effective portable multiplexing array prototype. In this perspective, the assessment of cost-effective manufacturability represents a crucial step, with specific regard to the optimization of the bio-functionalization protocol of the transistor gate module. Hence, we have assessed, using surface plasmon resonance technique, a sustainable and reliable cost-effective process to successfully bio-functionalize a gold surface, suitable as gate electrode for wide-field bioelectronic sensors. The bio-functionalization process herein investigated allows to reduce the biorecognition element concentration to one-tenth, drastically impacting the manufacturing costs while retaining high analytical performance.

Few binding events are here shown to elicit an extended work function change in a large‐area Au‐surface biofunctionalized with ≈108 capturing antibodies. This is demonstrated by Kelvin probe force microscopy (KPFM), imaging a ≈105 µm2 wide Au‐electrodes covered by a dense layer (≈104 µm−2) of physisorbed anti‐immunoglobulin‐M (anti‐IgM). A 10 min incubation in 100 µL phosphate buffer saline solution encompassing ≈10 IgM antigens (10−19 mole L−1  102 × 10−21 m) produces a work function shift ΔW ≈ –60 meV. KPFM images prove that this shift involves the whole inspected area. Notably, no work function change occurs upon incubation in highly concentrated (3 × 10−15 m) nonbinding IgG solutions. The ΔW measured by KPFM is in quantitative agreement with the threshold voltage shift of an electrolyte‐gated single‐molecule large‐area transistor (SiMoT). The findings provide direct experimental evidence for the SiMoT ultrahigh sensitivity, by imaging the extensive shift of the gate work function, likely arising from collective surface phenomena, elicited by single‐molecule binding events. A few antigen–antibody bindings generate an extended work function shift, assessed by Kelvin probe atomic force microscopy (AFM), in a large‐area biofunctionalized Au‐surface covered by 108 antibodies. This striking result compares with the threshold voltage shift measured by electrolyte‐gated single‐molecule transistor sensors and demonstrates that an amplification mechanism of the electrostatic change triggered by a few affinity binding events works even on a barely physisorbed biolayer.

A magnetically gated, enzymatically driven DNA release platform based on sustainable pyrolyzed walnut shell‐derived carbon electrodes is reported. Upon glucose addition under aerobic conditions, biocatalytic oxygen reduction at the cathode induces a local pH increase, resulting in electrostatic repulsion of negatively charged 5(6)‐carboxyfluorescein‐labeled DNA (FAM‐labeled DNA). Electrochemical analysis reveals an oxygen reduction reaction (ORR) onset potential of +0.576 ± 0.003 V vs. Ag/AgCl and a maximum current of −8.2 ± 0.4 μA. Electrochemical impedance spectroscopy (EIS) confirms a post‐ORR increase in interfacial resistance from 6.2 ± 0.5 to 11.1 ± 0.9 kΩ. DNA release reaches 97% after 400 min, corresponding to a surface density of 22 ± 4 nmol cm−2. A competing enzymatic gate, composed of co‐immobilized glucose oxidase and catalase (GOx–CAT) on magnetic nanoparticles (MNPs), enables remote suppression of electron flow and DNA release upon application of a 0.3 T magnetic field. Under “OFF” conditions, DNA release is reduced to 1%, and anodic current decreases by 60%. The system exhibits excellent reversibility over four ON–OFF cycles with minimal performance degradation. This bioelectronic platform represents a self‐powered, reversible strategy for stimuli‐responsive drug release. A magnetically actuated DNA release system using walnut shell‐derived electrodes enables ON/OFF switching of electron transfer by controlling DNA hybridization with magnetic beads.

The early detection of the human immunodeficiency virus (HIV) is of paramount importance to achieve efficient therapeutic treatment and limit the disease spreading. In this perspective, the assessment of biosensing assay for the HIV-1 p24 capsid protein plays a pivotal role in the timely and selective detection of HIV infections. In this study, multi-parameter-SPR has been used to develop a reliable and label-free detection method for HIV-1 p24 protein. Remarkably, both physical and chemical immobilization of mouse monoclonal antibodies against HIV-1 p24 on the SPR gold detecting surface have been characterized for the first time. The two immobilization techniques returned a capturing antibody surface coverage as high as (7.5 ± 0.3) × 1011 molecule/cm2 and (2.4 ± 0.6) × 1011 molecule/cm2, respectively. However, the covalent binding of the capturing antibodies through a mixed self-assembled monolayer (SAM) of alkanethiols led to a doubling of the p24 binding signal. Moreover, from the modeling of the dose-response curve, an equilibrium dissociation constant KD of 5.30 × 10−9 M was computed for the assay performed on the SAM modified surface compared to a much larger KD of 7.46 × 10−5 M extracted for the physisorbed antibodies. The chemically modified system was also characterized in terms of sensitivity and selectivity, reaching a limit of detection of (4.1 ± 0.5) nM and an unprecedented selectivity ratio of 0.02.

Background/Objectives: Multidisciplinary approaches spanning the physical, cognitive, and social domains of geriatric evaluation are essential to promote functional well-being and reduce the aversive consequences of aging. The main objective of the pilot study, “Multidomain Interventions to improve the COgnitive and fUNctional well-being of elderly individuals in residential sTructures” (I-COUNT), is to assess the feasibility of a 6-month multidomain intervention performed on older adults in Long-Term Care Facilities (LTCFs), compared with a group of residents following a traditional care approach. Methods: The intervention will involve two LTCFs in Italy and will include physical exercise and cognitive training, administered and monitored using wearable technologies, a nutritional program based on the Mediterranean diet enriched with selected functional foods, and the administration of the vaccinations recommended in the national vaccination plan. The I-COUNT study will assess the feasibility and acceptability of the defined protocol and provide information to determine the sample size for a definitive study. In relation to the potential health impact of multidomain interventions on older people living in LTCFs, the primary outcome will consider the change in microbiota composition assessed 3 months after the start of interventions, while secondary outcomes will include the evaluation of changes in selected biomarkers, physical performance, psychological health, cognitive functioning, and nutritional status at 6- and 9-month follow-up points. Conclusions: The I-COUNT study will allow us to assess the feasibility of delivering a multidomain intervention on elderly people. Exploratory findings on potential health effect will support the development of a larger-scale randomized controlled trial. Trial registration number: ClinicalTrials.gov ID NCT06820710.