Detection of chemical and biological agents plays a fundamental role in biomedical, forensic and environmental sciences1–4 as well as in anti bioterrorism applications.5–7 The development of highly sensitive, cost effective, miniature sensors is therefore in high demand which requires advanced technology coupled with fundamental knowledge in chemistry, biology and material sciences.8–13

In general, sensors feature two functional components: a recognition element to provide selective/specific binding with the target analytes and a transducer component for signaling the binding event. An efficient sensor relies heavily on these two essential components for the recognition process in terms of response time, signal to noise (S/N) ratio, selectivity and limits of detection (LOD).14,15 Therefore, designing sensors with higher efficacy depends on the development of novel materials to improve both the recognition and transduction processes. Nanomaterials feature unique physicochemical properties that can be of great utility in creating new recognition and transduction processes for chemical and biological sensors15–27 as well as improving the S/N ratio by miniaturization of the sensor elements.28

Gold nanoparticles (AuNPs) possess distinct physical and chemical attributes that make them excellent scaffolds for the fabrication of novel chemical and biological sensors (Figure 1).29–36 First, AuNPs can be synthesized in a straightforward manner and can be made highly stable. Second, they possess unique optoelectronic properties. Third, they provide high surface-to-volume ratio with excellent biocompatibility using appropriate ligands.30 Fourth, these properties of AuNPs can be readily tuned varying their size, shape and the surrounding chemical environment. For example, the binding event between recognition element and the analyte can alter physicochemical properties of transducer AuNPs, such as plasmon resonance absorption, conductivity, redox behavior, etc. that in turn can generate a detectable response signal. Finally, AuNPs offer a suitable platform for multi-functionalization with a wide range of organic or biological ligands for the selective binding and detection of small molecules and biological targets.30–32,36 Each of these attributes of AuNPs has allowed researchers to develop novel sensing strategies with improved sensitivity, stability and selectivity. In the last decade of research, the advent of AuNP as a sensory element provided us a broad spectrum of innovative approaches for the detection of metal ions, small molecules, proteins, nucleic acids, malignant cells, etc. in a rapid and efficient manner.37



Figure 1

Physical properties of AuNPs and schematic illustration of an AuNP-based detection system.



In this current review, we have highlighted the several synthetic routes and properties of AuNPs that make them excellent probes for different sensing strategies. Furthermore, we will discuss various sensing strategies and major advances in the last two decades of research utilizing AuNPs in the detection of variety of target analytes including metal ions, organic molecules, proteins, nucleic acids, and microorganisms.

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Gold nanoparticles in chemical and biological sensing.

The unique properties of gold nanoparticles have stimulated the increasing interest in the application of GNPs in interfacing biological recognition events with signal transduction and in designing biosensing devices exhibiting novel functions. The optical properties of GNPs provide wide range opportunities for construction optical biosensors. The excellent biocompatibility, conductivity, catalytic properties and high surface-to-volume ratio and high density of GNPs facilitate extensive application of GNPs in construction of electrochemical and piezoelectric biosensors with enhanced analytical performance with respect to other biosensor designs. In this article, the recent advances in construction of GNP-based optical, electrochemical and piezoelectric biosensors are reviewed, and some illustrative examples given, with a focus on the roles GNPs play in the biosensing process and the mechanism of GNPs for improving the analytical performances. Finally, the review concludes with an outline of present and future research for the real-world applications.

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Gold nanoparticle-based biosensors

Synthetic tuning of the catalytic properties of Au-Fe3O4 nanoparticles.

Biosensors and nanoscale analytical tools have shown huge growth in literature in the past 20 years, with a large number of reports on the topic of 'ultrasensitive', 'cost-effective', and 'early detection' tools with a potential of 'mass-production' cited on the web of science Yet none of these tools are commercially available in the market or practically viable for mass production and use in pandemic diseases such as coronavirus disease 2019 (COVID-19) In this context, we review the technological challenges and opportunities of current bio/chemical sensors and analytical tools by critically analyzing the bottlenecks which have hindered the implementation of advanced sensing technologies in pandemic diseases We also describe in brief COVID-19 by comparing it with other pandemic strains such as that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) for the identification of features that enable biosensing Moreover, we discuss visualization and characterization tools that can potentially be used not only for sensing applications but also to assist in speeding up the drug discovery and vaccine development process Furthermore, we discuss the emerging monitoring mechanism, namely wastewater-based epidemiology, for early warning of the outbreak, focusing on sensors for rapid and on-site analysis of SARS-CoV2 in sewage To conclude, we provide holistic insights into challenges associated with the quick translation of sensing technologies, policies, ethical issues, technology adoption, and an overall outlook of the role of the sensing technologies in pandemics

Opportunities and Challenges for Biosensors and Nanoscale Analytical Tools for Pandemics: COVID-19.

A novel electrochemical sensor was fabricated by electrodeposition of gold nanoparticle on pre-synthesized polypyrrole (PPy) nanowire, forming an Au/PPy composite matrix on glassy carbon electrode (Au/PPy/GCE). Field emission scanning electron microscope (FE-SEM), X-ray photoelectron spectroscopy (XPS) and powder X-ray diffraction (XRD) techniques were used for characterization of the composite. As an electrochemical sensor, the Au/PPy/GCE exhibited strongly catalytic activity toward the oxidation of hydrazine and hydroxylamine. The kinetic parameters such as the electron transfer coefficient (α) and charge transfer rate constant (k) for the oxidation of hydrazine and hydroxylamine were determined utilizing cyclic voltammetry (CV). The diffusion coefficient (D) of both two species was also estimated using chronoamperometry. Furthermore, the linear range, current sensitivity and detection limit for hydrazine and hydroxylamine were evaluated by differential pulse voltammetry (DPV). The detection limit of hydrazine and hydroxylamine was 0.20 and 0.21 μM (s/n = 3), respectively. In addition, the sensor showed excellent sensitivity, selectivity, reproducibility and stability properties.

Electrocatalytic oxidation of hydrazine and hydroxylamine at gold nanoparticle—polypyrrole nanowire modified glassy carbon electrode

Gold nanoparticle (Au-NP) seeds were adsorbed onto the surface of a self-assembled monolayer (SAM)-modified electrode. With the treatment of this modified electrode by Au-NPs growth solution containing different concentrations of H2O2 or cholesterol along with cholesterol oxidase (ChOx), the Au-NP seeds on the electrode surface were enlarged in varying degrees. As a result, the peak currents in corresponding cyclic voltammograms were inversely proportional to the concentration of H2O2 or cholesterol. ChOx was also further modified onto the surface of Au/SAM/Au-NP electrode to prepare Au/SAM/Au-NP/ChOx electrode. Using the enzyme-modified electrode to detect cholesterol, which also utilized the enlargement of the NPs, an extraordinary low detection limit of 5 × 10-9 M was achieved and two linear dependence ranges of 7.5 × 10-8−1 × 10-6 and 1 × 10-6−5 × 10-5 M were obtained. Consequently, new kinds of H2O2 and cholesterol biosensors could be fabricated.

Enlargement of Gold Nanoparticles on the Surface of a Self-Assembled Monolayer Modified Electrode: A Mode in Biosensor Design

Glucose and glutamine are two principal nutrients in mammalian cells that provide energy and biomass for cell growth and proliferation. Especially in cancer cells, glutamine could be a main alternative for energy and biomass supply once glucose metabolism is suppressed. Therefore, single inhibition of enzymes in either glucose metabolism or glutaminolysis, though maybe efficient in vitro, is far from being satisfactory for efficient in vivo cancer therapy. Here, we proposed a new strategy for dual inhibitions on both glucose and glutamine metabolisms concurrently by silencing mutated gene Kras and glutaminase 1 (GLS1) via nanomaterial-based siKras and siGLS1 delivery, rather than conventional highly toxic chemodrugs. Such a combination therapy could overcome the challenge that glucose and glutamine are alternatives to each other in the biosynthesis and energy production for cancer cells, resulting in much elevated treatment efficacy. In addition, layered double hydroxide (LDH), the siRNA carrier, enables an enhanced gene delivery efficiency compared to the commercial transfection agent Lipofectamine 2000. Briefly, Mg-Al LDH nanosheets, loaded with siKras and siGLS1 onto their surfaces by electrostatic adsorption, could release siRNA from lysosomes into the cytoplasm via the proton sponge effect of LDH, favoring the siRNA stability and gene silencing efficiency enhancements. The thus released siRNA could downregulate the expressions of Kras, GLS1, and other enzymes involved in glucose metabolism, resulting in the downregulations of ATP and other metabolites. Such a biosafe LDH/siRNA nanomedicine is able to efficiently suppress the growth of xenografts through cancer cell proliferation suppression, displaying its great potential as a simultaneous glucose/glutamine metabolism coinhibitor for treating pancreatic cancer.

Dual Inhibitions on Glucose/Glutamine Metabolisms for Nontoxic Pancreatic Cancer Therapy.

Abstract Tumor-associated bacteria (TAB) play a critically important role in regulating the microenvironment of a tumor, which consequently greatly deteriorates the therapeutic effects by chemo- and radiotherapy deactivation and, more considerably, leads to substantial immunosuppression. On the contrary, herein we propose a nanocatalytic tumor-immunotherapeutic modality based on the bacteria disintegration by bacteria-specific oxidative damage under magnetic hyperthermia for highly effective immune response activation-promoted tumor regression. A monodispersed and superparamagnetic nanocatalytic medicine modified by arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP), named as MNP-RGD-TPP herein, has been synthesized, which features selective accumulation at the TAB by the electrostatic affinity, enabling effective TAB disintegration by the nanocatalytic Fenton reaction producing abundant cytotoxic hydroxyl radicals in situ under alternating magnetic field-induced hyperthermia. More importantly, the lipopolysaccharide has been metabolically secreted from the destructed TAB as pathogen-associated molecular patterns (PAMPs) to M1-polarize tumor-associated macrophages (TAMs) and promote the maturation of dendritic cells (DCs) for innate immuno-response activation of TAMs, followed by cytotoxic T lymphocytes awakening under the PAMPs presentation by the mature DCs against tumor cells. The integrated innate and adaptive immunity activations based on this TAB-promoted nanocatalytic immunomedicine, instead of magnetic heating-induced hyperthermia or the released Fe2+/Fe3+ Fenton agent, has been found to achieve excellent therapeutic efficacy in an orthotopic colorectal cancer model, demonstrating the great potential of such an integrated immunity strategy in clinical tumor immunotherapy.

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Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer

Developing efficient and highly sensitive diagnostic techniques for early detections of pathogenic viruses such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) is vitally important for preventing its widespread. However, the conventional polymerase chain reaction (PCR)‐based detection features high complexity, excessive time‐consumption, and labor‐intensiveness, while viral protein‐based detections suffer from moderate sensitivity and specificity. Here, a non‐PCR but ultrasensitive viral RNA detection strategy is reported based on a facile nanoprobe‐coupling strategy without enzymatic amplification, wherein PCR‐induced bias and other shortcomings are successfully circumvented. This approach endows the viral RNA detection with ultra‐low background to maximum signal ratio in the linear signal amplification by using Au nanoparticles as reporters. The present strategy exhibits 100% specificity toward SARS‐CoV‐2 N gene, and ultrasensitive detection of as low as 52 cp mL−1 of SARS‐CoV‐2 N gene without pre‐PCR amplification. This approach presents a novel ultrasensitive tool for viral RNA detections for fighting against COVID‐19 and other types of pathogenic virus‐caused diseases.

Non‐PCR Ultrasensitive Detection of Viral RNA by a Nanoprobe‐Coupling Strategy: SARS‐CoV‐2 as an Example

Pancreatic cancer, with extremely limited treatment options and poor prognosis, urgently needs a breakthrough in early diagnosis and monitoring. Tumor exosomes (T-Exos) detection is presently one of the most clinically significant liquid biopsy approaches for non-invasive pancreatic cancer early diagnosis, which, unfortunately, cannot be applied as a routine diagnostic tool until a number of obstacles, such as unsatisfactory specificity and sensitivity, as well as labor-intensive purification and analysis procedures by ultracentrifugation and enzyme-linked immunosorbent assay, are overcome. Here, we report a facile nanoliquid biopsy assay for the especially specific, ultrasensitive yet economical T-Exos detection by a dual specific biomarker antigen co-recognition and capturing strategy, which is enabled by grafting two corresponding capture antibodies on magnetic nanoparticles and gold nanoparticles, for the accurate detection of target tumor exosomes. This approach exhibits excellent specificity and ultrahigh sensitivity of detecting as low as 78 pg/mL pancreatic cancer exosome specific protein GPC1. Successful screening of 21 pancreatic cancer samples from 22 normal control cases with the enhanced specificity and sensitivity ensures the promising non-invasive monitoring and diagnosis for early stage pancreatic cancer.

Zhiguo Yu

Papers

Enlargement of Gold Nanoparticles on the Surface of a Self-Assembled Monolayer Modified Electrode: A Mode in Biosensor Design

Dual Inhibitions on Glucose/Glutamine Metabolisms for Nontoxic Pancreatic Cancer Therapy.

Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer

Non‐PCR Ultrasensitive Detection of Viral RNA by a Nanoprobe‐Coupling Strategy: SARS‐CoV‐2 as an Example

Dual Tumor Exosome Biomarker Co-recognitions Based Nanoliquid Biopsy for the Accurate Early Diagnosis of Pancreatic Cancer.