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Field-effect transistors (FET) composed of transition metal dichalcogenide (TMDC) materials have gained huge importance as biosensors due to their added advantage of high sensitivity and moderate bandgap. However, the true potential of these biosensors highly depends upon the quality of TMDC material, as well as the orientation of receptors on their surfaces. The uncontrolled orientation of receptors and screening issues due to crossing the Debye screening length while functionalizing TMDC materials is a big challenge in this field. To address these issues, we introduce a combination of high-quality monolayer WSe2 with our designed Pyrene-based receptor moiety for its ordered orientation onto the WSe2 FET biosensor. A monolayer WSe2 sheet is utilized to fabricate an ideal FET for biosensing applications, which is characterized via Raman spectroscopy, atomic force microscopy, and electrical prob station. Our construct can sensitively detect our target protein (streptavidin) with 1 pM limit of detection within a short span of 2 min, through a one-step functionalizing process. In addition to having this ultra-fast response and high sensitivity, our biosensor can be a reliable platform for point-of-care-based diagnosis.

Nanopore sensors are expected to be one of the most promising next generation sequencing technologies, with label-free, amplification-free and high-throughput features, as well as rapid detections and low cost. Solid-state nanopores have been widely explored due to their diverse fabrication methods and CMOS compatibility. Here, we highlight the fabrication methods of solid-state nanopores, including the direct opening and the tuning methods. In addition, molecular translocation developments, DNA sequencing and protein detections are summarized. Finally, the latest progress relating to solid-state nanopores is discussed, which helps to offer a comprehensive understanding of the current situation for solid-state nanopore sensors.

The accurate detection of biological substances such as proteins has always been a hot topic in scientific research. Biomimetic sensors seek to imitate sensitive and selective mechanisms of biological systems and integrate these traits into applicable sensing platforms. Molecular imprinting technology has been extensively practiced in many domains, where it can produce various molecular recognition materials with specific recognition capabilities. Molecularly imprinted polymers (MIPs), dubbed plastic antibodies, are artificial receptors with high-affinity binding sites for a particular molecule or compound. MIPs for protein recognition are expected to have high affinity via numerous interactions between polymer matrices and multiple functional groups of the target protein. This critical review briefly describes recent advances in the synthesis, characterization, and application of MIP-based sensor platforms used to detect proteins.

Protein-protein interactions (PPIs) are critical to a range of biological processes and, consequently, aberrant interactions are implicated in many disorders. The study of the complex networks of PPIs promises to elucidate undiscovered roles in cellular processes and the mechanisms of disease. To accomplish this, tools to effectively sense PPIs are necessary. Effective PPI sensors must rapidly detect interactions in real-time with high sensitivity without perturbing the proteins of interest (POIs) under study. Split fluorescent proteins have previously been used to successfully monitor PPIs, in part due to the small size of the tags. Here, we developed an optimized tripartite split GFP system based on Corynactis californica GFP (ccGFP) to detect PPIs in vitro. In this sensor system, ccGFP fragments ccGFP10 and ccGFP11 are tagged to two POIs. PPIs can then be detected via fluorescence by complementation to the third fragment, ccGFP1-9, which reconstitutes functional ccGFP. The optimized ccGFP system shows improved detection kinetics and pH and temperature stability compared to a previous system. We then validated the sensor by monitoring PPIs in two model systems: attractive/repulsive coiled-coils and rapamycin-inducible FRB/FKBP heterodimerization. Finally, we developed an anti-tripartite ccGFP single-chain variable fragment (scFv), which could enable versatile detection of identified protein-protein complexes.

Proteins are widely regarded as insulators, despite reports of electrical conductivity. Here we use measurements of single proteins between electrodes, in their natural aqueous environment to show that the factor controlling measured conductance is the nature of the electrical contact to the protein, and that specific ligands make highly selective electrical contacts. Using six proteins that lack known electrochemical activity, and measuring in a potential region where no ion current flows, we find characteristic peaks in the distributions of measured single-molecule conductances. These peaks depend on the contact chemistry, and hence, on the current path through the protein. In consequence, the measured conductance distribution is sensitive to changes in this path caused by ligand binding, as shown with streptavidin–biotin complexes. Measured conductances are on the order of nanosiemens over distances of many nanometers, orders of magnitude more than could be accounted for by electron tunneling. The current is dominated by contact resistance, so the conductance for a given path is independent of the distance between electrodes, as long as the contact points on the protein can span the gap between electrodes. While there is no currently known biological role for high electronic conductance, its dependence on specific contacts has important technological implications, because no current is observed at all without at least one strongly bonded contact, so direct electrical detection is a highly selective and label-free single-molecule detection method. We demonstrate single-molecule, highly specific, label- and background free-electronic detection of IgG antibodies to HIV and Ebola viruses.

Nanosensors have a central role in recent approaches to molecular recognition in applications like imaging, drug delivery systems, and phototherapy. Fluorescent nanoparticles are particularly attractive for such tasks owing to their emission signal that can serve as optical reporter for location or environmental properties. Single-walled carbon nanotubes (SWCNTs) fluoresce in the near-infrared part of the spectrum, where biological samples are relatively transparent, and they do not photobleach or blink. These unique optical properties and their biocompatibility make SWCNTs attractive for a variety of biomedical applications. Here, we review recent advancements in protein recognition using SWCNTs functionalized with either natural recognition moieties or synthetic heteropolymers. We emphasize the benefits of the versatile applicability of the SWCNT sensors in different systems ranging from single-molecule level to in-vivo sensing in whole animal models. Finally, we discuss challenges, opportunities, and future perspectives.

Electrolyte-insulator-semiconductor (EIS) field-effect sensors belong to a new generation of electronic chips for biochemical sensing, enabling a direct electronic readout. The review gives an overview on recent advances and current trends in the research and development of chemical sensors and biosensors based on the capacitive field-effect EIS structure—the simplest field-effect device, which represents a biochemically sensitive capacitor. Fundamental concepts, physicochemical phenomena underlying the transduction mechanism and application of capacitive EIS sensors for the detection of pH, ion concentrations, and enzymatic reactions, as well as the label-free detection of charged molecules (nucleic acids, proteins, and polyelectrolytes) and nanoparticles, are presented and discussed.

Nanobodies, or VHHs, refer to the antigen-binding domain of heavy-chain antibodies (HCAbs) from camelids. They have been widely used as research tools for protein purification and structure determination due to their small size, high specificity, and high stability, overcoming limitations with conventional antibody fragments. However, animal immunization and subsequent retrieval of antigen-specific nanobodies are expensive and complicated. Construction of synthetic nanobody libraries using DNA oligonucleotides is a cost-effective alternative for immunization libraries and shows great potential in identifying antigen-specific or even conformation-specific nanobodies. This review summarizes and analyses synthetic nanobody libraries in the current literature, including library design and biopanning methods, and further discusses applications of antigen-specific nanobodies obtained from synthetic libraries to research.

Van der Waals (vdW) heterostructures composed of atomically thin two‐dimensional (2D) materials have more potential than conventional metal‐oxide semiconductors because of their tunable bandgaps, and sensitivities. The remarkable features of these amazing vdW heterostructures are leading to multi‐functional logic devices, atomically thin photodetectors, and negative differential resistance (NDR) Esaki diodes. Here, an atomically thin vdW stacking composed of p‐type black arsenic (b‐As) and n‐type tin disulfide (n‐SnS2) to build a type‐III (broken gap) heterojunction is introduced, leading to a negative differential resistance device. Charge transport through the NDR device is investigated under electrostatic gating to achieve a high peak‐to‐valley current ratio (PVCR), which improved from 2.8 to 4.6 when the temperature is lowered from 300 to 100 K. At various applied‐biasing voltages, all conceivable tunneling mechanisms that regulate charge transport are elucidated. Furthermore, the real‐time response of the NDR device is investigated at various streptavidin concentrations down to 1 pm, operating at a low biasing voltage. Such applications of NDR devices may lead to the development of cutting‐edge electrical devices operating at low power that may be employed as biosensors to detect a variety of target DNA (e.g., ct‐DNA) and protein (e.g., the spike protein associated with COVID‐19). In this article, the authors report an atomically thin vdW stacking of “b‐AS/SnS2,” to build a type‐III (broken gap) heterojunction, leading to a negative differential resistance (NDR) device. The hexagonal surface of SnS2 offers an ideal plate‐form of π–π stacking for supporter molecules composed of a “pyrene ring” loaded with “lysine‐biotin” to detect the “streptavidin” biomolecules as analytes.

It is of great significance to establish sensitive and accurate pathogen detection methods, considering the continuous emergence or re-emergence of infectious diseases seriously influences the safety of human and animals. Proximity ligation assay (PLA) is developed for the sensitive protein detection and also can be used for the detection of pathogens. PLA employs aptamer or monoclonal/polyclonal antibody-nucleic acid complexes as proximity probes. When the paired proximity probes bind to the same target protein or protein complex, they will be adjacent to each other and form an amplifiable DNA sequence through ligation. Combining the specificity of enzyme-linked immunosorbent assay (ELISA) and sensitivity of polymerase chain reaction (PCR), PLA transforms the detection of protein into the detection of DNA nucleic acid sequence. Therefore, as an ultrasensitive protein assay, PLA has great potential for quantification, localization of protein, and clinical diagnostics. In this review, we summarize the basic principles of PLA and its applications in pathogen detection.Key Points• Different forms of proximity ligation assay are introduced.• Applications of proximity ligation assay in pathogen detection are summarized.• Proximity ligation assay is an ultrasensitive method to quantify protein and pathogen.