key: cord-0807279-8h9i3mgs authors: Tanimoto, Izadora Mayumi Fujinami; Cressiot, Benjamin; Greive, Sandra J.; Le Pioufle, Bruno; Bacri, Laurent; Pelta, Juan title: Focus on using nanopore technology for societal health, environmental, and energy challenges date: 2022-05-20 journal: Nano Res DOI: 10.1007/s12274-022-4379-2 sha: 91e0e7b29916200e1f685d4b0dd8825898b777dd doc_id: 807279 cord_uid: 8h9i3mgs With an increasing global population that is rapidly ageing, our society faces challenges that impact health, environment, and energy demand. With this ageing comes an accumulation of cellular changes that lead to the development of diseases and susceptibility to infections. This impacts not only the health system, but also the global economy. As the population increases, so does the demand for energy and the emission of pollutants, leading to a progressive degradation of our environment. This in turn impacts health through reduced access to arable land, clean water, and breathable air. New monitoring approaches to assist in environmental control and minimize the impact on health are urgently needed, leading to the development of new sensor technologies that are highly sensitive, rapid, and low-cost. Nanopore sensing is a new technology that helps to meet this purpose, with the potential to provide rapid point-of-care medical diagnosis, real-time on-site pollutant monitoring systems to manage environmental health, as well as integrated sensors to increase the efficiency and storage capacity of renewable energy sources. In this review we discuss how the powerful approach of nanopore based single-molecule, or particle, electrical promises to overcome existing and emerging societal challenges, providing new opportunities and tools for personalized medicine, localized environmental monitoring, and improved energy production and storage systems. [Image: see text] The growing global economy and population pose numerous current and future challenges for humanity. Access to affordable health care, environment conservation, and sustainable, abundant, and low-cost sources of energy is some of the key challenges faced by our society. Despite recent slowing in growth rate, the current global population will rise from 7.7 to 9.7 billion people by 2050 [1] , further increasing the already high demand for affordable health care, energy, arable land, as well as clean air and water. Health care provision faces additional challenges due to the increasing average age of the global population. A panoramic view shows a demographic trend for population ageing that is predicted to rise rapidly planetwide. By 2050, the world population aged over 60 will likely reach 2 billion people, compared to 900 million in 2015, a doubling of the population proportion. Today, 125 million people are aged 80 and over, and by 2050, there will be 434 million people in this age group [2] . Ageing impacts health through the increase in chronic diseases, such as diabetes, hypertension, and cancer, but will also lead to an increase of neurodegenerative diseases such as Alzheimer's and Parkinson's. This is compounded by unexpected global events such as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic that has depressed the global economy through decreased manufacturing, disrupted supply chains, reduced productivity, and overwhelmed health systems [3] . The rapid global spread and severity of illness obliged the entire world to respond quickly to this new challenge. Since 2019, novel coronavirus disease (COVID-19) has been responsible for at least 5.6 million deaths worldwide. The World Bank Group estimates that the global gross domestic product only reached $84 trillion in 2020 and $87 trillion in 2021, a cumulative loss of more than $10 trillion compared to the situation that would have prevailed without the covid pandemic [3] . The total economic cost of this recession could be even higher and difficult to estimate, due to the long-term effects on health, investment, and education. The consequences of such current and future health challenges are significantly increased by the ageing population, which has global impact by affecting general economic productivity, as well as, increasing the need for access to affordable health care. Emission of pollutants from fossil fuel-based energy production, agriculture, and industry is progressively impacting our environment, with 12.6 million deaths in 2012 estimated to be due to environmental pollutant effects [4] . These emissions also induce global climate changes [5] and natural disasters which affect the entire planet, from soils to oceans, with catastrophic renewable energies represent only a few % of current global energy consumption, in part due to the unpredictable nature of the weather and tides that power many of these sources [20] . Costeffective and efficient energy storage methods would counter this unpredictability in supply, however, up to now, the world storage capacity is about 1% of global consumption. The transition towards an ideal zero CO 2 emission in 2050, "climate neutral", or at least a drastic reduction of emission, requires numerous changes in energy generation, use, and storage. These goals include the use of primary energy from renewable energies to recharge the battery storage facilities [21] . Technological advances are providing some solutions to these societal challenges and continued innovation and development of new technology will contribute to management and mitigation of future challenges that arise. As part of this technology-based management, there is a general need to develop monitoring systems that are highly sensitive, in-situ, and low-cost, and have single molecule sensing capabilities. Indeed, the lower level of detection sensitivity will allow integration with tightly controlled feedback retroaction, leading to a higher level of safety and efficacy in personalized medicine, environmental control, and energy production, management, and storage. Nanopore technology provides a solution for these sensing challenges. It is based on a resistive pulse sensing (RPS), where a decrease of the ionic conductance of a nanohole is detected when a single molecule or nanoparticle passes through. This approach based on electrical detection through a nanopore was designed by H. Coulter in 1953 [22] . The electrical detection is optimized in terms of signal to noise ratio when the size of the pore is on the same order as that of the analyte. One of the greatest advantages is the possibility to synthesize different types of nanopores from natural and artificial materials [23] [24] [25] [26] targeted to the environmental conditions and the size of the species under study. The electrical signature is sensitive to size, conformation, sequence, chemical nature, and/or charge of the molecule, as well as the nature of ions in the electrolyte solution. Nanopore sensing does not require imaging equipment nor amplification, as in the case of the gold-standard reverse transcription-polymerase chain reaction (RT-PCR). Therefore, it allows the system to scale down to a portable level, like the MinION, developed by Oxford Nanopore Technologies (ONT). Thus, this powerful single molecule technique has great potential to help address the different current and future societal challenges. In this review, we will focus on nanopore studies that have had, or will have, significant impacts on the fields of health, environment, and energy storage. We first focus on cancer diagnostics through nucleic acid, protein, peptide biomarkers, and virus detection, as well as organic molecule and drug detection. We present approaches to characterize the size and composition of the nanoparticles in the environment disseminated by natural or human activities. We also look at the potential for blue energy and for smart battery diagnosis by nanopore sensing. We conclude this short review with a discussion about the potential perspectives for addressing many of the current and future societal challenges with nanopore technology. Since the 90's, there has been a strong effort from the nanopore community to answer biological questions and to address health challenges. Many of these studies were conducted in vitro, using biomolecules, and not necessarily connected to direct applications, but were needed from a fundamental aspect to enhance the technology. This review will only focus on concrete results showing how nanopore technology has been applied to health challenges. As presented in Fig. 1 , we will discuss a non-exhaustive list of work describing how nanopores can be used for cancer diagnostics and as powerful detectors for protein biomarkers, viral genomes, and particles, as well as organic molecules. Nanopore technology has been initially focused on nucleic-acid sequencing [35] . While in 1996, the first results were published on DNA transport through an alpha-hemolysin nanopore [36] , it was only in 2015 that an Escherichia coli (E. coli) genome was assembled de novo with 99.5% accuracy using ONT's MinION [37] . Regarding the cancer context, nanopore sequencing has been mainly used to detect structural variants [38, 39] or deletions, inversions, and translocations on tumor suppressor genes in pancreatic cancer [40] . Mutation detection of the TP53 gene has also been explored in patients with chronic lymphocytic leukemia [41, 42] . A wide variety of cancer-related genes such as EGFR, KRAS, NRAS, and NF1 in lung adenocarcinoma have also been sequenced to explain anti-tumor drug sensitivity and resistant mutations [43] . As shown in Fig. 1 (1)(a), nanopore technology has been employed to detect and sequence circulating tumor DNA (ctDNA) from a liquid biopsy [27] . This ctDNA harboring the mutations of the original tumor permits the establishment of a molecular diagnosis for cancer monitoring, early-stage detection, and assisting targeted therapy. The authors used a new technique called CyclomicsSeq, where ctDNA is circularized with an optimized backbone. Rolling circle amplification generates a long DNA molecule with alternative insert and backbone sequences. Identifying mutations in the TP53 gene versus assay DNA polymerase induced errors and sequencing artifacts are discriminated by using consensus calling of the DNA sequence. Nanopores have also been used to detect miRNAs that are short non-coding polynucleotides (an average of 20 nucleotides length). Their differential expression and specific sequences are involved in the initiation and evolution of human cancer [44] . Furthermore, these short miRNAs can be released from a primary tumor into the blood [45] . Figure 1 (1)(b) shows that such miRNAs from blood [28] can be detected and identified via a nanopore without amplification using a complementary sequence probe tag for cancer detection. An electrical signature has been observed to detect miR-155 in the plasma of healthy volunteers and patients with lung cancer. The number of events is proportional to the miRNA concentration, which depends on the expression level of this biomarker. The signature frequency for miR-155 hybridized to the probe is higher for patients with lung cancer, and the signal is sensitive up to 0.1 pM. Wanunu et al. showed in another study using a solid-state nanopore [46] that the signal can be sensitive up to 1 fM. Additionally, nanopore technology has demonstrated the ability to detect epigenetic modifications such as CpG methylation, one of the earliest epigenetic biomarkers for cancer [47] [48] [49] . Protein and peptide detection by nanopore has been extensively studied at a fundamental level. The nanopore community focused their work on understanding the transport dynamics of proteins/peptides through nanopores [50] [51] [52] [53] [54] [55] , aptamers, and nanopore modifications to control protein capture and selectivity [51, [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] . This review focuses only on biomarker detection, the list provided above is not an exhaustive one of what has been published. Nanopore technology is only recently expanding to protein and peptide biomarkers detection. Biomarkers used for medical analysis are indicators of normal biological and pathogenic processes and are used to assess the risk or presence of disease, pharmacological responses, or course of therapeutic intervention [67] . Up to now, only four publications have shown the potential for these biomarkers [29, 30, 64, 68] . Several recombinant proteins such as endothelin, chymotrypsin, angiotensin, or EGF were detected using an engineered FraC protein nanopore [30] . The other studies used indirect detection methods such as DNA carriers to detect thrombin and acetylcholine from serum using a nanopipette [64] ; and to detect prostatic specific antigen bound to DNA aptamers [68] or thyroid stimulating hormone (TSH) with a digital assay [29] using solid-state nanopores ( Fig. 1 (2)(a)). The presence of TSH is simply detected when two dumbbells linked by a junction are detected through a solid-state nanopore. The authors could quantify TSH from human serum down to the pM range. Regarding peptide biomarker detection, to the best of our knowledge, there is only one major study showing the potential of nanopore technology to sense peptides with different protein nanopores. Huang et al. used a mutated FraC nanopore with a controllable diameter to discriminate Angiotensin I, II, III, and IV [30] (Fig. 1 (2)(b)). The authors showed that they were able to sense each peptide that differed by only a few amino acids. This study is for now the most complete one for peptide biomarker sensing with 17 peptides analyzed. On the other hand, those peptides were not sensed in a complex biofluid. The ongoing outbreak of the COVID-19 caused by SARS-CoV-2 has raised a major public health concern worldwide, in which, high-throughput and high-accuracy detection are needed to control these diseases outbreaks. Nanopore sensing generates realtime sequencing data with the potential to become a point-of-care assay. This technique has been already used to identify pathogens, such as chikungunya virus (CHIKV) [69] , Ebola virus (EBOV) [31, 69] , hepatitis C virus (HCV) [69] , human metapneumovirus (HMPV) [70] , influenza [71] , Lassa fever [72] , and SARS-CoV-2 [73] using Oxford Nanopore Technology within a 6-10 h timeframe. In 2015, researchers used this nanopore technology to provide a real-time genomic surveillance during the EBOV outbreak in West Africa [31] . They provided a robust analysis approach, where it was possible to survey the virus variants ( Fig. 1 (3)(a)), in which the sequencing process took as little as 15-60 min. This is one of the first steps towards personalized medicine. The individual genetic profile can be used to identify and monitor signatures of viral evolution and drug resistance mutations. This guides the decisions made in regard of diagnosis and characterization of responses to treatments. Moreover, the same system was implemented in the resurgence of the virus last year, providing further insight into the genomic make-up of the viruses [74] . Since polymerase-based assays rely on virus specific primer design that requires prior sequence knowledge, which is unavailable when a new viral outbreak occurs, nanopore sequence technology was crucial in the diagnosis and management of SARS-CoV-2 infections during the first months of the pandemic [75] . The current gold-standard RT-PCR requires highly trained personnel, dedicated facilities, and instrumentations, being time consuming and with limited testing capability. Therefore, to increase test accessibility, other alternatives are necessary. A study using reverse transcription loop-mediated isothermal amplification (RT-LAMP) coupled with a glass nanopore was able to detect SARS-CoV-2 with 98% diagnostic sensitivity and 92% diagnostic specificity [76] . Many publications since SARS-CoV-2 pandemic were published showing the detection of variants by performing complete genome and phylogenetic analysis [73, [77] [78] [79] [80] . Bull et al. even describe highly accurate consensuslevel sequence determination, with single-nucleotide variants detected at > 99% sensitivity and > 99% precision above a minimum ~ 60-fold coverage depth, thereby ensuring suitability for SARS-CoV-2 genome analysis and confirming the suitability of ONT sequencing for standard phylogenetic analyses. However, the extraction of viral RNA can be time consuming and presents a risk of exposure to the technician. Solid-state nanopores can have their diameter tuned to match the size of the target nanoparticle providing direct detection of the virus particles. Recently, a method has been reported using a solid-state nanopore in combination with artificial intelligence to detect, in vitro, the individual virions from several types of respiratory viruses ( Fig. 1 (3)(b)) with a discrimination of more than 99% accuracy [32, 81] . Later, this approach was used to detect these viruses in biofluid. In saliva specimens, the authors demonstrated a sensitivity of 90% and specificity of 96% with a 5-min time frame [32] . Furthermore, the use of machine learning technology can be used to discriminate different types of viruses [82, 83] , which will enable the development of point-of-care devices with high sensitivity, accuracy, and throughput. Since its development in the 90's, nanopore technology has been quickly used to detect drugs and organic molecules. In 1999, the first demonstration of sensing organic molecules was achieved using an alpha-hemolysin modified by a cyclodextrin inserted into its lumen [84] . This cyclic sugar reduced the diameter of the pore so that the authors were able to discriminate between promethazine and imipramine. By modifying alpha-hemolysin, other studies showed the potential for sensing mustard gas analogues [85] . In order to design new or improve existing antibiotics, experiments were conducted to understand how antibiotics can enter bacteria [86] . Several bacterial porins and their mutants were analyzed for a better understanding of antibiotic translocation through these channels and proved to be useful to characterize the physicochemical rules of porin-mediated permeability. Figure 1 (4)(a) shows how Kawano et al. designed a methodology for the rapid and highly selective detection of cocaine using alpha-hemolysin combined with a DNA aptamer [33] . The DNA aptamer recognizes the cocaine molecule with high selectivity. When the aptamer is bound to a cocaine molecule, the complex is trapped inside the nanopore, exhibiting a specific signal. The authors detected a low concentration of cocaine (300 ng·mL −1 ) within 60 s using this pore embedded in a microchip. Most of the studies cited above did not detect these molecules from a biofluid. A recent publication showed the potential to directly detect organic molecules such as glucose and asparagine from biofluids (sweat, urine, saliva, and blood) using a protein nanopore ClyA (Fig. 1(4) [34] . The system relies on two specific glucose and asparagine protein binders. The proteins having different conformations when bound or unbound to their substrate, the authors were able to sense the conformational state of each binder and quantify indirectly both organic molecules. Our environment contains a huge diversity of nanoparticles ( Fig. 2 (1)), which can be discriminated in terms of size (1-1,000 nm), and material, that can be natural materials (e.g., pollen, SiO 2 , volcanic ashes, and sulfur gases...), or human made materials (e.g., TiO 2 [87, 88] , SiO 2 [89, 90] , Ag + [9, 88, [91] [92] [93] , and micro-and nano-plastics [6, 7, 94, 95] ). Nanoparticles produced by human-made materials are unfortunately linked to a market with an estimated size in billions of dollars (TiO 2 $20.9 billion in 2021 [96] , SiO 2 $6.45 billion in 2018 [97] , and silver $2 billion in 2020 [98] ). TiO 2 is used in several industrial fields and enters the composition of paintings, paper, plastic, or cosmetics as a white pigment. These particles are found, for example, in algae [87] , or bacteria [88] . SiO 2 is found in nature as quartz, which is one of the most common minerals on earth and is extracted from sand or granite. It is mainly used in architecture and is a compound in concrete for construction. It also plays an important role in the composition of glass or ceramics. Silica nanoparticles are used in chemistry, pharmaceutics, and the food industry. After purification, they are one of the main materials for the high-tech industry of microelectronics or fiber optics. SiO 2 nanoparticles also have cytotoxic properties due to the presence of silanol groups. They can interact with membrane proteins leading to cell damage of the immune system [90] . Their environmental impact has been shown by several publications [89] . Silver nanoparticles are used for their antibacterial properties in biomedicine, and food packaging industry [9, 92] . Toxic effects of small Ag nanoparticles (< 25 nm) could be due to their antibacterial nature and damage to important bacterial biofilms [88, 91] . Moreover, Ag nanoparticles in their cationic form can be dissolved and interact with anions such as citrates to induce crossover toxicity [88, 92, 93] . Nanoparticles in air are analyzed by condensation particle counters (CPC) [101] to measure their concentrations, size distributions, and charges. To discriminate the different shapes, high resolution microscopy is needed such as scanning electron microscopy (SEM) or transmission electron microscopy (TEM) [88, 102] . Atomic force microscopy (AFM) is also able to analyze shapes of nanoparticles or nanofibers [103] or their charge [104] . These devices allow study of the interaction between nanoparticles and lipidic nanotubes [105] and can be supplemented by electrical characterization of lipid bilayer membranes in the presence of nanoparticles [106] . Nanoparticles in solution could be also analyzed by dynamic light scattering (DLS) [88, 107] . However, these sensing methods need to be combined, in order to accurately measure concentration, size, shape, and chemical or charge composition. These methods are expensive and are mainly confined to laboratories, demanding infrastructures, and highly qualified technicians. While still in the early stage of development, we present below a nanopore sensing electrical approach that promises to provide a low-cost, highly sensitive, portable, and realtime monitoring system for nanoparticle pollution. As described above, RPS is based on electrical detection through a confined constriction playing the role of the sensing head ( Fig. 2(2) ), which can be optimized for the target nanoparticles. This technology enables both numeric and size analyses of single 90 nm large polystyrene nanoparticles through high aspect-ratio (length L >> radius R) pores in a Nuclepore tracketched membrane [108] . Recently, Balme et al. have designed single track-etched pores to detect 40-100 nm large polystyrene nanoparticles [109] . In 2004, Ito et al. have shown a single long carbon nanotube was able to both analyze size and surface charge of functionalized polystyrene particles [110] . Electron beam lithography has enabled the fabrication of very low aspect-ratio (L << R) 100 nm-1 μm sized pores in 50 nm -1 μm thick membranes of Si [111, 112] or SiN x membranes [100, 113] for the detection of 50-800 nm large polystyrene or gold nanoparticles. The medium aspect-ratio pores (L ≈ R) are obtained by drilling 20-100 nm thin membranes. The material used to make these membranes is mainly SiN x , but SiO 2 can also be used for the analysis of carboxylate modified 100-200 nm nanobeads [114] or 11 nm × 68 nm gold nanorods [115] . Promising materials such as hafnium oxide for 10 nm gold nanoparticle sensing [115] or titanium nitride, titanium-tantalum and tantalum have also been used to detect 100 nm polystyrene nanoparticles coated with DNA [116] . The largest nanopores (135-300 nm) are drilled in 50-500 nm thick membranes by focused ion beam (FIB) milling for the detection of single particles on the scale of silicate [99, 117] , latex [118, 119] , gold [120] , and polystyrene [121, 122] nanoparticles. Smaller nanopores below 40 nm are drilled by an electron beam issued from a TEM to optimize the sensing of nanoparticles below 10 nm [115, 123] . The statistical analysis of current blockade experiments is mainly based on the blockade rate, duration, or amplitude. The blockade rate allows the nanoparticle concentration to be estimated according to the amplitude of the energy barrier that must be crossed to enter the nanopore [99, 116] . The amplitude is a function of the nanoparticle size or shape [99, 108, 110, 123] . The duration makes it possible to describe the transport dynamics through the nanopore [99] . As the transport is mainly controlled by a difference of applied potential, the charge [99, 112, 123] or the electrophoretic mobility [110] can also be evaluated. In the case of neutral nanoparticles, the flow rate is governed by a difference of applied pressure such as hydrostatic [118, 124] or osmotic pressure [30] . A recent publication has shown an interesting microfluidic device to capture nanoparticles disseminated in air (Fig. 2(3) ). This method allows discrimination between cedar and cypress pollens from their current blockades and duration distributions [100] . Machine learning algorithms can be used to determine which pair of parameters is relevant to identify the different pollen types and can be generalized to the detection of other particles [62, 125] . In all cases, a microfluidic architecture to be combined with the nanopore detector is crucial in theses monitoring systems, not only to manage the fluid handling and delivery to the nanopore, using specific surface functionalization [56, 57] , but also to include pre-filtering functions or fluid addressing functions for high throughput approaches [126] , or even to stabilize the nanopore and its lipid bilayer microenvironment in case of biological nanopores [127] . The fast growth of global energy consumption and the need to limit the effects of global climate change through transition from fossil fuel-based energy production require new energy sources. Renewable energy plays an important role in reducing greenhouse gas emissions, associated with global warming. It allows the conservation of natural resources, lowers carbon emission, and avoids contamination of air and water. As the name suggests, it is created from natural sources such as sunlight [128] , wind [129, 130] , biomass [131] , geothermal [132] , and water salinity gradients [133] [134] [135] [136] [137] . The latter, also known as blue energy, present a promising energy source if we consider the availability of energy coming from the osmotic pressure difference between seawater and fresh water or wastewater [136] . The two most promising methods to harness the salinity gradient energy are i) pressure-retarded osmosis (PRO) [138, 139] , a water flow through semipermeable membranes (Fig. 3(1)(a) ), and ii) reverse electrodialysis (RED) [140] [141] [142] , which uses ion-exchange membranes (IEMs) (Fig. 3(1)(b) ). The main difference between them relies on the molecule being transported through the semiporous membrane that is composed by an array of nanopores, water, or ions, respectively. Up to now, their major limitations are their low energy efficiency, and the cost and fouling of membranes [137, 143, 144] . The semipermeable membranes do not have an adequate water flow [145] . The membrane support present an internal concentration polarization, which considerably reduces permeate-water flux, thus reducing the power density. A pilot plant in Norway could generate less than 1 W·m −2 using commercial, asymmetrical cellulose-acetate membranes [145] . Thus, the development of new materials and techniques are fundamental. Recently, ion-selective nanochannels have been exhibiting promising results to harvest blue energy (Fig. 3(1)(c) ) [146, 147] . Siria et al. showed that boron nitride nanotubes (BNNTs) present an enhancement of the osmotic current, reaching a power density about 4 kW·m −2 for a single BNNT using a RED configuration (Fig. 3(2)(a) ) [148] . Later on, a two-dimensional (2D) single-layer molybdenum disulfide (MoS 2 ) nanopore reached a power density about 1 MW·m −2 in alkaline solution [149] . These studies report an increase in the magnitudes of energy generated. Recently, nanoporous carbon membranes made from core-rim polycyclic aromatic hydrocarbons reached a maximum value of 67 W·m −2 with a cationic selectivity [150] . The technique used paves a way to large-scale fabrication of nanopores arrays with a small pore size distribution and a good ionic selectivity. Changes in the nanochannel size and shape can also optimize its performance. A study comparing different types of nanochannels: bullet-shaped, conical, and trumpet-shaped nanochannels, reported that trumpet-shaped nanochannels presents the best ion selectivity while the bullet-shaped one presents a local maximum of power harvesting [133] . As cited before, MoS 2 monolayer membranes provided one of the best efficiencies in producing energy. By increasing their surface charge with light irradiation, it is possible to double the osmotic power generated using a single nanopore at neutral pH ( Fig. 3(2)(b) ) [147] . Batteries, as one of the most versatile energy storage technologies, play a central role in the ongoing transition from fossil fuels to renewable energy [19] . They have become key enablers for the deployment of electric transportation and the use of decentralized renewable energy sources. With batteries becoming the heart of future society, generation of smart batteries should support this change in the energy economy and is a fundamental element of sustainable development [151, 152] . A key feature of such battery design is the incorporation of smart functionalities, for example, sensing and diagnosis [153] , self-healing and recovery [154] to increase the initial lifespan, to allow reconditioning for reuse, to develop and manufacture more eco-compatible battery, and to recycle battery elements as much as possible. Indeed, there is a crucial need to improve their quality, reliability, and life by noninvasive in operando performance monitoring and control of their state of health, state of charge, state of energy, state of power, and state of safety [153] . The principle of a rechargeable battery is an electrochemical cell composed of a cathode and an anode, positive and negative electrodes respectively, separated by an ion-containing electrolyte solution. Electrodes are connected to an electrical circuit that allows the electron flow, while the ion flow is only possible through the electrolyte. Simultaneous electrochemical reactions occur at the two electrodes, leading to the charge (energy storage) As water flows into the HC chamber, the pressurized solution propels a hydro turbine to generate energy. (b) Schematic of RED configuration. In RED, the energy is generated by the concentration difference across IEMs, in which, cation-exchange membranes (CEMs) and anion-exchange membranes (AEMs) are stacked alternately between the low and high concentration solutions. The ion flux, positive ions moving one way and the negative ones moving in the counter direction, creates an electrochemical difference that is converted into an electrical current at the electrodes and a work is produced by the load resistor, generating energy. (c) Schematic of harvesting osmotic energy with a negative charged solid-state nanopore. Electrolytes with different salt concentration are separated by a nanopore membrane. A mostly positive charged ion flux is driven by the chemical potential through the negatively charged nanopore. (2) Osmotic power generation under salinity gradients with nanopores. (a) Osmotic streaming current versus concentration difference for a transmembrane boron nitride nanotube (t-BNNT) with {R, L} = {40 nm, 1,250 nm} and pH 5.5 (yellow), 9.5 (purple), and 11 (red). The experimental points show measurements for various salt concentrations (C) in the two reservoirs, with C min and C max in the range 10 −3 -1 M. Error bars follow from the corresponding error analysis. Dashed lines are linear fits for measured osmotic current: I osm = K osm log(C max /C min ). Inset, osmotic mobility (K osm ) versus surface charge. Surface charge is obtained from independent conductance measurements. The dashed line is a linear fit: K osm ≈ 0.33Σ, where Σ is the surface charge density on the BNNT surface. Reproduced with permission from Ref. [148] , © Macmillan Publishers Limited 2013. (b) Current vs. voltage (I-V) characteristics at a concentration gradient of 1:1,000 using different laser intensities. Reproduced with permission from Ref. [147] , © Elsevier Inc. 2019. (Created with BioRender.com) and the discharge of the battery (energy delivery), depending on the electron flow direction [155] (Fig. 4(1) ). One of the challenges in the energy storage field using batteries is the ability to sense, with high specificity and high sensitivity, the health state of a battery for diagnostic analysis either during cycling or post-mortal analysis [153] . The next step will be to cure (2) Detection of parasitic species using a protein nanopore. (a) Schematic of the ion-current measurement set-up. One protein nanopore is inserted into a suspended lipid bilayer. An electrical potential is applied via two Ag/AgCl electrodes, which induces an ionic current of Na + and Cl − ions through the nanopore (1 M NaCl, 25 mM NaHCO 3 , pH 10, under argon atmosphere). At pH 10, the α-HL is anion selective, consequently, an EOF directed from trans to cis sets in favoring the entry of β-cyclodextrin and Na 2 S x /β-cyclodextrin into the stem part of the α-HL. (b) Detail of a part of current trace blockades arising from β-cyclodextrin (blue) and from Na 2 S 5 /β-cyclodextrin complex (red) interaction with the pore at −100 mV. battery degradation by self-healing functions [154] . Moreover, selfhealing is a natural evolutionary process of living organisms, to repair diverse types of damage to increase their lifetime. The kinetics of this process is between minutes to months, respectively for blood coagulation and bone fissure or fracture repair. The performance and lifetime of many rechargeable batteries are limited by two main problems, (I) mechanical degradation: electrode cracking, silicon anode degradation, electrical contact loss, and chemical and (II) electrochemical degradation: electrolyte degradation/formation of solid electrolyte interphase (SEI), lithium plating/dendrite formation, gas evolution, metal dissolution, and degradation of inactive components (binders, separators, and current collectors). Several approaches are being developed to limit battery degradation, for example, self-healing binders, polymers, electrolytes, artificial SEI, the use of microcapsules for the vectorization and the deliverance of conductive additives, and the design of smart separators [154] . We discuss now the ability, in the future, to apply nanopore technology to Li-ion battery diagnostics in order to prevent their degradation and to improve their performance. For energy storage and conversion, the conception of new electrochemical devices compatible with sustainable development has become essential. Indeed, there is a need to develop electrode materials with potential higher capacity and based on abundant materials. This has motivated concerted research efforts towards new systems beyond Li-ion, for instance the Li-sulfur battery with five times more theoretical specific energy (Wh·kg −1 ), significantly improving the size/weight to energy capacity ratio, an important consideration in electric transportation [156] . Although quite appealing, this system suffers from poor performances associated with difficulties in mastering-limiting the polysulfide (polyS) redox shuttle process [157] . Redox shuttles are also responsible for part of the capacity decay observed in today's Li-ion batteries. This capacity loss is due to polysulfide solubility (S 8 2− , S 6 2− , etc.) in the electrolyte. These chemical species result from reduction of sulfur by lithium. This step is necessary to get the fully reduced and insoluble Li 2 S. Polysulfide can then diffuse to the Li 0 electrode, be reduced there, and passivate the surface of the negative electrode. This process consumes sulfur, the active material of the positive electrode. Furthermore, the longest polysulfide chains can be only partially reduced on the Li 0 surface and diffuse back to the positive electrode where they can be oxidized again. Such a back-and-forth process is known as redox shuttle. Interesting analytical techniques already exist to identify redox species and monitor, for instance, Li-S batteries electrolyte composition [158] such as ultraviolet-visible (UV-vis) spectra [159] , differential cyclic voltammetry [160] , nuclear magnetic resonance (NMR) [161] , X-ray [162] , mass spectrometry [163] , fiber Bragg grating sensors [164] , or tilted sensors [165] . These techniques are useful, but expensive, and some of them require infrastructure and operational expertise. The bulk approach does not allow detection of the size, sequence, or chemical reaction, at the single molecule level, of these parasitic redox species at the beginning of their formation. Recently the proof-of-concept has been shown, in aqueous medium, to identify polyS species with a protein nanopore and using a cyclodextrin (CD) adaptor [166] . Na-based polysulfide species Na 2 S n (n = 3, 4, and 5) in aqueous media can be found as catholyte in aqueous Na-ion/polysulfide batteries [157] . The best affinities for β-CD-polysulfides complexes are found in comparison to alpha and gamma-CD, the interaction is reversible by temperature. Only one molecule of polyS is inside the cavity of the CD. The affinity increases with the polysulfide length in the complexation. The CD alone or the complex enters toward the stem side of alpha-hemolysin by the electro-osmotic flux (EOF) driving force contribution (Fig. 4(2)(a) ). The blockade ratios from the current traces show a specific signature for each species of polysulfide (see Fig. 4 (2)(b)). This signature is mainly due to the steric volume of the complex inside the nanopore (Fig. 4 (2)(c)). A good correlation is obtained between the blockage ratio and the pore hindrance estimator. Finally, this work demonstrated polysulfide detection and discrimination, with single sulfur resolution, in aqueous medium using a protein nanopore. One of the next challenges in the future is to implement the nanopore approach in battery conditions. Up to now, it is impossible to work with a biological membrane and nanopore, mainly composed of lipids, in organic solvent. Several options are possible, such as the use of a polymer membrane [167, 168] or a solid-state membrane [26] to design a hybrid nanopore [169] [170] [171] . Protein channels are hardly used in non-aqueous mediums. It is therefore necessary to find or to design new class of highly stable protein nanopores. Different polymers can be used to manufacture track-etched membranes in order to make them resistant to multiple solvent conditions [168] . It is possible to control the pore density in the membrane from a single nanopore up to 10 10 pore·cm −2 , the pore diameter nanometric to micrometric and also the thickness of the membrane ranging from 6 to 50 μm [168] . Recently, polyethylene terephthalate (PET) membranes containing nanopores have been designed and used as a separator for Li-S coin cells battery to increase their performance [172] . The PET separator is sandwiched between two Celgard 2400 membranes soaked with electrolyte. The separator is inserted between the Li anode and the carbon-sulfur cathode (Fig. 4(3) ). By cycling only 15 times, the Coulombic efficiency is maintained of up to 97% with minor reduction in capacity as a function of nanopore diameter and density used. We observe that most of the attention from the nanopore community had been focused on societal health challenges. Due to devices and application protocols from Oxford Nanopore Technologies, rapid nucleic-acid sequencing by nanopores has become routine. We saw that researchers adapt the sequencing system for better accuracy or specific identification of mutations in genes implicated in cancer. The portable MinION sequencer offers the prospect of personalized medicine, such as the example given with Ebola surveillance [31, 74] or recently seen in SARS-CoV-2 diagnosis and genome analysis [75, 173] . The nanopore technique is extremely powerful in detecting organic molecules and shows promising results in searching for biomarkers in infinitesimal (high femtomolar range) [29] quantities from biofluids [34] . On the other hand, the technique could still lack sensitivity and selectivity to directly detect a biomarker in a complex fluid without microfluidic pre-filtering or a molecular carrier. Regarding proteins, only a tiny percent of the human genomic DNA encodes for them. Additionally, protein isoforms, variants, and chemical modifications are not coded in the genome either. The resulting protein diversity is deeply involved in normal and diseased cellular processes. We are at the start in detecting proteins and peptides as biomarkers and in a race to design protein sequencers by nanopores [174, 175] . Cellular protein information, often used as a source of biomarkers, is of great importance for early disease detection. Recent publications showed that actual nanopores are sensitive enough to identify amino acid composition [30, [176] [177] [178] [179] and posttranslational modifications [180] [181] [182] [183] , opening a new era in proteomics. Researchers are also exploring protein fingerprinting [184] . The idea relies on measuring peptide spectra produced from hydrolyzed proteins, such as seen in mass spectrometry, allowing their identification. A recent publication also showed that a DNA-peptide conjugate could be pulled through a protein nanopore MspA by a DNA helicase Hel308 allowing multiple rereads in the ionic current signal enabling discrimination of single-amino acid substitutions in single reads [185] [186] [187] . This proof-of-concept opens excellent prospects for sequencing proteins and peptides. One of the societal issues in health that has not been addressed in this review is understanding the processes of protein aggregation in neurodegenerative diseases such as Alzheimer's disease and how to prevent this pathological aggregation. Some studies have been able to follow this dynamic of aggregation in vitro by nanopore with recombinant proteins, mainly using artificial, track-etched, and glass nanopores [51, [188] [189] [190] . On the other hand, no study has been conducted using biological material from patients to date. The nanoparticles released into the environment are disseminated in the air, soil, and water. Eventually, we find them in the food we eat or in the air we breathe. Several analytical techniques must be combined in a laboratory with highly qualified people to characterize the concentrations, sizes, shapes, or composition of each nanoparticle. Based on electrical sensing at the nanoparticle level, the RPS approach can meet this challenge as it was the case for nano-plastic or silicate nanoparticle. Nevertheless, this technique should be extended to TiO 2 and silver nanoparticles to follow environment pollution. Until now, these RPS devices remain confined to the laboratory. In the future, they will be used, in situ, near the source of pollution in the air or along the river by taking the design of portable devices into account. As these sensors require low energy, they could be inserted in autonomous devices to monitor environments in real time when connected to a wireless network. A similar approach based on the confined transport of ions will be used to produce renewable, clean, and non-intermittent source of energy, to answer the increase in energy consumption caused by economic and population growth, if we want to preserve the planet for future generations. The energy conversion coming from salinity gradients, also known as blue energy, has been explored as a promising immense and untapped source of energy. However, the large-scale implementation of PRO and RED system has been hindered by the low efficiency of the current harvesting technology, mainly due to the low power density at scales beyond the ones produced in laboratories. Advances in the material science and nanofluidic transport reported findings of extremely high osmotic power densities, which could further be increased using nanopore arrays along the membrane or using natural sources (e.g., sunlight) to generate charges along the membrane surface to optimize power generation. Beyond developing new ways to produce energy, there is a need to increase storage capability of the current batteries. Nanopore technology also offers solutions to this challenge. The approach to health diagnostics and personalized medicine could continue to inspire the field of energy storage with a new generation of batteries that must conform to sustainable development. Thus, it would be necessary to be able both to perform a diagnosis of the state of health of a battery and to be able to repair in situ the degradation. To heal batteries, it will be necessary to add repair functions integrated into the battery that are activatable according to a stimuli related to a threshold of battery degeneration. Considerable work remains to be done for the detection and characterization of parasitic species in batteries and to probe the chemical reactions associated with the formation of these species, even if the proof-of-concept has just been shown, in an aqueous environment, on the ability of a nanopore to identify parasitic species, polysulfides, with a discrimination resolution of a single sulfur and the ability to complex them with cyclodextrins [166] . It will be a huge challenge, for several reasons, to design and synthesize the required materials to manufacture the nanopores according to the specifications of the harsh battery environment. In addition, there is work remaining to integrate such an electrical sensor into a battery. Another, less complex approach would be to proceed by taking samples during the operating cycles of the battery life, but also for post-mortem analysis. The coupling between electrical detection with nanopore sensor and damage repair is also a perspective to be developed in the upcoming years. It will be interesting to manufacture smart separators that could early detect and identify parasitic species to capture them effectively. In particular, the functionalization of polymeric membranes could provide a solution. In this review, we discuss how the nanopore technique, based on single-molecule, or particle, electrical sensing affords methods to address many of the existing and emerging societal challenges in health care, environmental monitoring, and energy provision or storage. Indeed, the success of nanopore genome sequencing as a tool to manage health, including the SARS-CoV-2 pandemic, one of the greatest health challenges faced by humanity in the last century, is proof of the potential power of nanopore electrical sensors as solutions for emerging and future societal challenges. This technology will provide tools for the development of highly sensitive, real-time, integrated, or on-site sensing to monitor personal health, environmental emissions, and battery health in new smart battery designs. This technology has great potential in applications such as blue energy harvesting and self-healing smart batteries to provide reliable sources of renewable energy for the growing global economy and population. In summary, nanopore technology, along with other innovations, will contribute to the global maintenance of affordable healthcare, clean air and water, arable land, and cheap renewable energy. 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