Applications of nanomaterials as treatments and diagnostic biosensors in microbial infections

Abstract

Microbial infection is a major medical problem that seriously threatens public health. The abuse of antibiotics that help evolve the emergence of new drug‐resistance mechanisms has led to the wide‐spread and fast expansion of drug‐resistant bacteria, ultimately evolving into superbugs. This significantly impairs the timely and effective treatment of infections, thus threatening global human well‐being. Not all are pessimistic. Nanomaterials have emerged as an innovative choice. Due to their unique physical and chemical properties, superior bactericidal effects, and high biocompatibility, nanomaterials may help eradicate drug‐resistant bacteria to achieve complete remission of infectious diseases. As biological materials, nanomaterials can also improve the efficacy of existing drugs and treatments and even facilitate diagnostic efficiency. In this review, we aim to comprehensively summarize the antibacterial properties of different kinds of nanomaterials and their applications in other spheres related to treating infectious diseases (targeted therapy, phototherapy, vaccine development, and microbial diagnosis). We highlight the latest advances of nanomaterials in treating infectious diseases in different body systems. Finally, we conclude by discussing the weaknesses of currently available materials and unresolved scientific problems, which may provide insights into the development of approved agents that adequately overcome the notorious drug resistance and thereby provide unprecedented discoveries to improve treatments of the most severe bacterial infections.

INTRODUCTION

Bacterial infection is one of the most common infectious diseases and a constant thorn harming human well-being. Bacteria enter different tissues and organs of the human body, thereby causing damage to the function of organs. For example, a bacterial infection of the lungs can cause diseases such as tuberculosis (TB) and pneumonia. Bacteria entering the urinary tract may cause urinary tract infections with frequent urination and urgency symptoms. Furthermore, severe bacterial infections may also spread throughout the body, leading to multiple organ dysfunction syndrome, sepsis, septic shock, and ultimately mortality.

Antimicrobials are medicines with antibacterial or bactericidal activity that can prevent and/or treat infections. However, with the improper use or abuse of antibiotics, antibacterial drug resistance is becoming more and more common and increasingly serious.¹ To combat the host immune system and drugs' antimicrobial activities, bacteria have natural and acquired resistance to the drug action through various mechanisms, including the production of modified enzymes, the active elimination of drugs via the efflux pump mechanism, and the aggregation and formation of biofilms.² Some bacteria have even emerged as multidrug resistances or, ultimately, super-drug resistances called superbugs. Therefore, it is a severe and urgent task for contemporary medical research to design new methodologies or materials to screen and develop new antibacterial agents with broad spectrum and superior antibacterial efficiency.³

Nanomaterials have unique properties such as large surface area to volume ratios, photochemical properties, antibacterial effects, and high biocompatibility. Currently, applications of nanomaterials include the use of nanoparticles as therapeutic agents, drug delivery, and diagnostic vectors. Compared to conventional antimicrobial agents, these nanomaterials can directly kill microorganisms or help improve the efficacy of existing therapeutics and reduce side effects through their precise targeting mode or other actioning mechanisms. Some nanomaterials have intrinsic antibacterial properties (metals, carbon, some organic matter), which can prevent the adhesion of bacteria to avoid biofilm formation or kill bacteria through diverse mechanisms.⁴ In addition, nanomaterials can be used as carriers of antibiotics to release high concentrations of drugs at the site of infection, achieving targeted and powerful bacterial killing.⁵ However, nanomaterials may have toxic effects on the human environment and other adverse effects.⁶ Therefore, more research is in the making, focusing on improving the biological safety of nanomaterials.⁷

In this review, we attempt to describe the recent development of nanomaterials and their applications. We discuss antimicrobial properties of currently available nanomaterials and explore the applications of antibacterial nanomaterials such as microbial diagnosis, phototherapy, and vaccine development. Finally, we focus on the latest advances in nanomaterials in treating clinical diseases and propose some opinions according to the shortages of currently available nanomaterials and unresolved scientific problems.

NANOMATERIALS AND ANTIMICROBIAL PROPERTIES

Different nanomaterials have been fabricated and tested as antibacterials by exerting different bactericidal mechanisms (Figure 1), which are described below.

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Metal-based nanomaterials

Metal-based nanomaterials are new molecular aggregates composed of several metal atoms, which exert antibacterial primarily through three mechanisms: first, they induce cell membrane/cell wall damage through adsorption and osmosis, resulting in changes in the permeability of the cell membrane⁸; second, metal ions are released, which interact with nucleic acids or proteins in cells and then interfere with the homeostasis of intracellular components and metabolic pathways⁹; and third, these materials induce intracellular reactive oxygen species (ROS) production and kill cells through cellular oxidative stress response.¹⁰ Physicochemical properties of metal-based nanomaterials size, appearance, and surface modification played a crucial part in the antibacterial activity.

Noble metal-based nanomaterials

The capability of noble metals (gold and silver) nanoparticles to provide antimicrobial effects has been demonstrated since their excellent surface-to-volume ratio, which induces physiochemical changes like the occurrence of surface plasmon resonance and production of ROS species mechanism.

Silver nanoparticles (AgNPs), mainly with antibacterial activity may be through significant antibiofilm activity by breaking cell membranes and being potent against biofilm colonization and cell adherences.¹¹ Additionally, AgNPs smaller than 10 nm can penetrate the cell membrane, cause changes in the permeability of the cell membrane, interrupt cellular processes through the increase of ROS and the release of Ag⁺, and then lead to cell death.^12,13 However, the released Ag⁺ by AgNPs is toxic to human cells when killing bacteria, which not only induces inflammation and oxidative stress at the exposed site, but also crosses various biological barriers and enters the systemic circulation, causing pathophysiological reactions in the human body. The problem of bacterial drug resistance remains. For example, Gram-negative bacteria develop drug resistance by producing flagellin, which leads to aggregation of AgNPs and efflux pump action.^14,15

Compared to AgNPs, Gold nanoparticles (AuNPs) with large areas are chemically inactive but can exert antibacterial efficacy as antibiotic carriers. When the size of AuNPs decreases to ultrasmall sizes (typically smaller than 2 nm), these gold nanoclusters (AuNCs) can cross cell membranes and produce intracellular ROS, leading to metabolic imbalances that kill bacteria consequently.¹⁶ Additionally, AuNPs combined with various surface ligands have spawned different applications as medical treatment owing to their high biocompatibility, ease of modification, and stability. However, due to the inert nature of gold, its antibacterial activity is relatively limited.

Considering the above-described drawbacks, several solutions have been proposed to increase their antibacterial activity, including adjusting the material's size, adding surface modifications, and forming composite nanomaterials. Different sizes of nanomaterials hold various advantages, so there are pH-sensitive AgNPs with the benefits of both small and large size, which can target and cross the cell membrane by forming small-size AgNPs. Their self-aggregation ability can persistently destroy bacterial biofilms for a relatively long time by forming large-size AgNPs.¹⁷ A common modification method is phenylboronic acid modification, which can promote the selective aggregation of bacteria. The development of noble metal nanocomposites exhibited prospective opportunities to achieve efficient antibacterial activities, improve histocompatibility with human cells, and solve the problem of bacterial drug resistance. For example, silver combined with cyano graphene overcomes the problem of bacterial drug resistance by effectively resisting the aggregation of AgNPs induced by flagellin, and the low leaching rate of Ag⁺ improves histocompatibility with human cells.¹⁸

Metal oxide-based nanoparticles

The most promising and widely studied are metal oxide-based nanoparticles with interesting biological properties like obvious magnetic behavior, chemical stability, and biocompatibility. A comparative analysis of magnesium oxide nanoparticles (MgONPs), cupric oxide nanoparticles (CuONPs), iron oxide nanoparticles (IONPs), zinc oxide nanoparticles (ZnONPs), and nanocomposites of oxides was conducted below.

CuONPs exhibit great antibacterial potential, while their toxic mechanisms to different cell types can hamper the clinical use of CuONPs as antibacterials. Therefore, surface functionalization of CuONPs, such as surface carboxylation, surface pegylation, and chitosan coupling, is often performed to improve safety while maintaining its antibacterial properties.^19–21 IONPs are promising antimicrobial agents with low toxicity to eukaryotic cells and high biocompatibility. Using the particular property of magnetism to create artificial channels in infectious biofilms, IONPs can improve permeability and enhance the killing ability of an antimicrobial against bacteria.²² In addition, these materials can be recycled while maintaining antibacterial activity through IONPs magnetism. ZnONPs bear unique fluorescence properties, so they can transfer electrons to Staphylococcus aureus driven by visible light, leading to the pathogen inactivation.²³

Carbon-based nanomaterials (CNMs)

CNMs, including carbon nanotubes, graphene/graphene oxide, fullerenes, and nanocomposites, show minimal cytotoxicity to eukaryotic cells when used alone, so they are considered the next generation of prospective antibiotics. CNMs may exert their antibacterial mechanism mainly in the following ways.^24,25 First, they invade the microbial cell wall/membrane, induce structural damage, and some CNMs with large surface areas can wrap microbial cells and isolate them from their supportive environment; second, the interaction of CNMs with bacteria induces oxidative stress response via the production of ROS; and third, the oxidative stress unrelated to ROS is generated as the electron transfer is established related to bacterial interaction, leading to biological death.

Carbon nanotubes

Carbon nanotubes are a potential antibacterial nanomaterial causing cell damage by directly contacting the cell membrane of bacteria. In a liquid medium, carbon nanotubes with narrow diameters (<1 nm) can cross cell membranes and cause bacteria breakdown. Compared to the randomly oriented carbon nanotubes, recent studies have shown that vertically aligned carbon nanotubes as antibacterial surfaces can have specifical targeting, which are easily modified for antibacterial applications.²⁶

Graphene-based nanomaterials

Graphene is a kind of two-dimensional CNMs with broad-spectrum antibacterial activity, including graphene oxide (GO), reduced graphene oxide (rGO), and graphene-based composite nanomaterials. Graphene comes into direct contact with bacteria through its sharp edges that cause physical damage to cell membranes and leakage of cell contents.²⁷ In addition, GO has the highest catalytic activity because of the more substantial charge transfer effect, which enables it to pass through the energy barrier on the surface of the cell membrane.

However, GO also presents some problems, like cytotoxicity and bacterial drug resistance. When eukaryotic cells are exposed to high concentrations of GO for a long term, it is shown to induce physical damage to cell membranes and ultimately causes cell death.²⁸ Meanwhile, antibiotic resistance emerges due to prolonged exposure to low concentrations of GO.²⁹ At present, multiple studies have been published to show that problems can be transformed by adjusting the size, morphology, or surface modification of GO. Isomerism-structured GO show the different antibacterial effect that bacteria are more vulnerable to physical puncturing of vertically aligned graphene because of their bladelike effect. Subsequently, it was found that graphene-coated silicon substrate showed significantly higher activity against Gram-negative bacteria than SiO₂ substrate, which may be caused by the difference in electrical conductivity.³⁰ Combining metal or organic polymers with graphene-based composite is another approach. There was a synergistic effect between S-GQDs and AgNPs, so a nanocomposite consisting of AgNPs decorated with sulfur-doped graphene quantum dots (QDs) serves as a promising antibacterial agent for their strong antibacterial activities and high biocompatibility.³¹ In addition, lanthanum hydroxide and GO (La@GO) have synergistic antibacterial properties against drug-resistant Escherichia coli without inducing new resistance.³²

Carbon QDs

QDs have unique intrinsic properties that can generate free radicals under UV light irradiation and subsequently induce oxidative stress response of bacteria.³³ Graphene, GO and carbon QDs are common types of QDs with a good deal of therapeutic effect. The antibacterial activity of QDs can be enhanced by targeted surface modification like quaternary ammonium groups, tartaric acid, and aminophenol.³⁴

Organic nanomaterials

Compared to inorganic nanomaterials, organic nanomaterials have better biocompatibility. The antibacterial mechanisms proposed and tested are still controversial, and the following two ways are the prevailing opinions: (1) adsorb on bacteria through the action of electric charge and change the permeability of bacterial cell membrane; (2) block bacterial life activities by coupling with metal ions necessary for transcription and translation. In addition, organic nanomaterials can hinder the formation of biofilms and degrade mature biofilms through certain physical or biochemical mechanisms, like the interaction of positive and negative charges.³⁵

Antimicrobial peptides (AMPs) are a vital part of the innate immune system that sticks to the surface of bacteria to resist the formation of biofilms and inhibit the synthesis of protein and nucleic acid.³⁶ Binding polymers to AMPs can increase their water solubility and resistance to proteases, which showed significantly enhanced broad-spectrum bactericidal activity and promising biocompatibility. The prevailing approach to play a synergistic antibacterial role is to change their composition. Coating the AuNPs with AMPs enables the materials to neutralize the charges of the two, making them negligible mammalian cell toxicity in an electrically neutral environment. However, when these AMPs touched the bacterial cell membrane, charge conversion occurred to rapidly kill bacteria.³⁷

Chitosan is a polysaccharide derived from chitin, which has high biocompatibility and antibacterial activity. Due to the poor water solubility and high viscosity of purified chitosan, modifying chitosan with surface functional groups (quaternization, alkylation, phosphorylation, and acylation) is used to expand its application. Chitosan modified with the quaternary ammonium group can improve the antibacterial activity of chitosan by the positive charge, but excessive quaternization may enhance the cytotoxicity of nanomaterials.³⁸ Surface alkylation of chitosan can prevent the formation of broad-spectrum biofilms, while phosphorylated chitosan demonstrates good biocompatibility and can promote tissue regeneration.³⁹ Different degrees of acetylation of chitosan lead to changes in the positive charge density of the chitosan chain, which alters the antibacterial activity.

Hydrogel is a kind of giant polymer with a three-dimensional network structure, including chitosan hydrogels, sodium alginate hydrogels, and cellulose hydrogels, which are popularly used in targeted therapy but also can be adjusted by modifying and crosslinking with metal ions to exert certain antibacterial activity. Cellulose crosslink with Ca²⁺ holds good biocompatibility and biodegradation,⁴⁰ and sodium alginate can be crosslinked with Ca²⁺, Zn²⁺, and other metal ions to form hydrogels, which has more vigorous antibacterial activity of the composite than that of the single material.⁴¹ In addition, trehalose-based nanoparticles can act as antiadhesive agents, preventing bacteria from adhering to the host cells and causing infection.⁴² And due to the trehalose's unique mechanism, it is difficult for bacteria to timely develop resistance to it, which has broad research prospects.

Nanozymes

Nanozymes are a kind of nanomaterials possessing intrinsic enzyme activity, whose advantages of easy synthesis and modification, high catalytic activity and good biocompatibility make them superior to natural enzymes. Thus far, various nanozymes with different structures and compositions have functions of antibacteria and antibiofilms. The nanozyme family can be divided into two categories⁴³: nanozymes with oxidoreductase enzyme activity and nanozymes with hydrolase activity (nuclease, esterase, phosphatase, protease).

The nano-enzyme family of oxidoreductase is more widely studied and applied. They catalyze O₂ and H₂O₂ to generate ROS under acidic conditions, which in turn cause irreversible damage to bacteria, including destroying the active components of microorganisms, leading to drastic changes in bacterial morphology and catalyzing the degradation of molecules in the biofilm matrix to eliminate the biofilm.⁴⁴ Some metal-based nanoparticles and CNMs have been found to possess the properties of natural oxidase and peroxidase (POD), which are used for biocatalytic reactions and antibacterial treatments. Only a small part of the research has focused on nanozymes with hydrolytic enzyme activity, which can cut chemical bonds in biomacromolecules and further hydrolyze bacterial biofilms. By analyzing the data of existing hydrolytic nanozymes, researchers designed the hydrolytic nanozymes based on Ce-FMA-MOF, which could hydrolyze a broad scope of substrates, including phosphoric acid bonds, amide bonds, and glycoside bonds.¹⁷

However, most nanozymes have the following problems: They cannot selectively interact with cells; and the ROS produced has a short existence life and diffusion distance, leading to limited catalytic activity. Hence, composite materials are discovered to overcome these deficiencies while maintaining the activity of nanozymes. Metal-organic frames (MOFs) with POD-like activity and multiple clear active sites can prevent the polymerization of small molecule NPs and thus improve the stability of nanozymes. There are MOF/Ce-based nanozymes with the simulated activities of DNase and POD. The Ce complex bound to MOFs exhibited DNase activity, resulting in biofilm disintegration and bacteria exposure, while MOF provided multiple active sites and POD activity, improving the hydrolytic activity of Ce.⁴⁵

Targeted molecular modifications on the surface of nanozymes and changes in the morphology and size of nanoparticles can also serve as a solution. Reducing the diameter of nanoparticles can better expose the active sites and improve the catalytic activity, and when the nanomaterials are reduced to the level of a single atom, they show clear active centers and superior catalytic properties.⁴⁶ However, since nanomaterials tend to accumulate naturally, it is not easy to obtain ultrasmall nanoparticles. Thus, a new type of two-dimensional (2D) MOFs is proposed as a carrier with ultra-thin thickness, which can accelerate the movement speed of nanozymes and overcome the problem of long diffusion distance. Furthermore, the incorporation of ultra-micro Au nanoparticles onto 2D MOFs can effectively prevent the agglomeration of AuNPs.⁴⁷ In addition, changes in the external environment, such as the presence of natural organic matter, affect the antibacterial behavior of nanozymes. After interacting with humic acid, the oxidation-like activity of Pd@Ir significantly increased, inducing the level of ROS to rise, thus significantly enhancing the bactericidal activity of these nanostructures.⁴⁸

NANOMATERIALS AND MICROBIAL DIAGNOSIS

During the past decades, conventional bacterial detection methods (plate separation culture, serological methods, molecular biology techniques) have been developed continuously, but there are some defects, like time-consuming and laborious. Compared with conventional methods, nanomaterials are able to produce efficient and sensitive microbial detection due to their unique characteristics (high surface-volume ratio, good biocompatibility, and special chemical properties). According to the types of signal transducers, nanomaterial-based microbial detection methods can be divided into optical, electrochemical, and so on (Figure 2). Finally, we discuss point-of-care testing (POCT) devices and machine learning-assisted sensor arrays.

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Optical biosensor

Optical biosensors can detect the optical signal sensitively when the bioreceptor recognizes and binds to the target biomolecules. Based on various detection modes, optical biosensors are mainly divided into three aspects: colorimetric, fluorescence, and surface-enhanced Raman scattering (SERS)-based detection (Table 1). We will cover all these aspects in this series.

Table 1 Optical biosensors based on different nanoparticles.

Recognition methods	NP composition	Identified bacteria	Recognition element	Limit of detection	Detection range	Ref.
Colorimetric
Electrostatic interaction	AuNPs	Urease-producing bacteria	NH3	101 cells/mL	/	[49]
Chitosan	Staphylococcus aureus, Escherichia coli	/	105 cfu/mL	/	[50]
Antibody-guided methods	AuNPs and IONPs	S. aureus	/	10 cfu/mL	10–106 cfu/mL	[51]
Colloidal gold-based ICST	Yersinia enterocolitica O:8	/	1.3 × 103 cfu/mL	/	[52]
Antibody-guided and Van-modified	Fe3O4@SiO2–Pt	S. aureus	d-Ala–d-Ala moieties	101 cfu/mL	/	[53]
Aptamer-guided	Ap−starch@ZIF-90	Different types of pathogenic bacteria	miRNA or DNA	/	/	[54]
Phage-guided	AuNPs	E. coli, Pseudomonas aeruginosa, Vibrio cholerae, Xanthomonas campestris	/	~100 cells	/	[55]
Colorimetric and fluorescent
Electrostatic interaction	UIO@MB	E. coli O157: H7	/	103 cfu/mL	/	[56]
Fluorescent
Electrostatic interaction	Eu@SiNPs	Bacillus anthrax	Spores	/	/	[57]
Antibody-guided methods	GO and GQD	Campylobacter jejuni	/	10 cfu/ml	/	[58]
Antibody-guided methods and Van-modified	CuNCs	S. aureus	/	80 cfu/mL	102–108 cfu/mL	[59]
Aptamer-guided methods	QDs	Helicobacter pylori	DNA	/	/	[60]
CuNCs	S. aureus	MNase	1.0 mU/mL	1.0 × 10−3–5.0 × 10−2 U/mL	[61]
Aptamer-guided methods and Van-modified	AuNCs	S. aureus	/	10 cfu/ml	20–108 cfu/mL	[62]
Van-modified	Cu2−xSe and NaGdF4:Nd, Yb@ DCNPs	Gram-positive bacteria	/	/	/	[63]
Functionalized with a glucose polymer	SiNPs	S. aureus, P. aeruginosa	/	105 cfu	/	[64]
SERS
Electrostatic interaction	G@AgNPs@Si	E. coli, S. aureus	ATP	~1 pM	/	[65]
Au@Ag	S. aureus, E coli, Shigella dysenteriae, P. aeruginosa, Klebsiella pneumonia	The bacterial surface protein and glycan signals	101 cfu/mL	/	[66]
AgNPs+	S. aureus, Candida albicans, B. cereus, E. coli, P. aeruginosa	/	/	/	[67]
Antibody-guided methods	GO@Au	S. aureus	/	8 cells/mL	/	[68]
E. coli O157:H7	10 cells/mL
Salmonella typhimurium	10 cells/mL
Aptamer-guided methods	AuNPs	S. typhimurium	/	35 cfu/mL	102–107 cfu/mL	[69]
Fe3O4@SiO2-Au	E. coli, S. aureus	/	10 cfu/mL	10–108 cfu/mL	[70]
Au/Ag nanodimer	S. typhimurium	/	50 cfu/mL	102–107 cfu/mL	[71]
S. aureus	96 cfu/mL	3.2 × 102–3.2 × 107 cfu/mL

Colorimetric nanosensors

Colorimetric detection is the simplest method to get optical signals generated by the target, which obtains direct qualitative observation through human naked eyes or quantitative analysis by UV-visible absorption spectrometry (UV-Vis). Depending on the role of different NPs, they can be divided into target-induced aggregation or dispersion and chromogenic substrate-mediated catalytic activity. It is worth noting that interparticle plasmonic coupling between NPs results in a redshift in the UV-Vis spectrum, subsequently accompanied by changes in the color of the system. For example, scattered spherical AuNPs appear burgundy in solution, while clustered AuNPs change color from red to blue with increasing diameter, so this characteristic is widely utilized to detect analytes.⁷² NPs have an enzyme-like activity that can alter colorimetric reactions by catalyzing chromogenic substrates, such as TMB, and some pH indicators.⁷³ In addition, effectively capturing and immobilizing bacteria are essential for improving the selectivity and specificity of bacterial detection. For instance, NPs can adhere to the surface of bacterial walls through electrostatic interaction; and functionalized NPs (antibodies, aptamers, bacterial toxins, phages, etc.) can be targeted to attach to receptors/proteins/epitopes expressed on the surface of target bacteria.⁷⁴

Fluorescent nanosensors

Fluorescence nanosensors are one of the most common optical technologies for pathogenic bacteria detection, and they are well known for their advantages of high sensitivity and efficiency. Fluorescence occurs when an excited molecule or nanomaterial emits light in reverting to its ground state, so many fluorophore donors and acceptors are often developed as part of fluorescence resonance energy transfer (FRET)-based biosensors.⁷⁵ FRET is the nonradiative transfer of excess energy between an excited state molecule (donor) and an acceptor substance. When FRET occurs, fluorescence quenching can be easily observed. During bacteria detection, the target bacteria are the key to fluorescence change from quenching to restoring, also known as turn on/off mode. QDS are common fluorophore donors and acceptors with powerful spectral absorption properties, high brightness, and photostability. A fluorescent immunosensor consisting of GO and graphene QDs conjugated with monoclonal antibodies was used to detect Campylobacter jejuni quantitatively. In the presence of C. jejuni, the interaction between monoclonal antibodies and surface proteins lead to generating a certain distance between the graphene dots and GO, causing the graphene dots to turn on fluorescence emission. And the fluorescence intensity increases with the number of bacterial target cells.⁵⁸ Nanoparticles doped with lanthanide (Ln³⁺) can be used as fluorescence probes in the near-infrared (NIR) region II (1000−1700 nm), which can be modified to increase the target signal and achieve high signal-to-noise ratio imaging.⁶³

SERS-based detection

SERS is a new technique derived from Raman spectroscopy, with the advantages of rapid detection, high sensitivity and specificity, simple data processing, and no influence by photobleaching. When molecules are adsorbed on the surface of rough metals or metal nanoparticles, the Raman spectral signal of the molecules will be significantly improved due to the local surface plasmon resonance and the “hot spot” effect so that individual molecules can be detected.⁷⁶ Currently, two main approaches to detecting bacteria are SERS sensors, called label-free and label-based strategies.

For the label-free method, the SERS spectra originate from mutual interaction between bacteria and SERS substrate. Methicillin-resistant S. aureus (MRSA) can be identified accurately and aggregated effectively using assembled AgNPs⁺ as the SERS substrate, which provides higher-quality and reproducible SERS fingerprinting spectra.⁶⁷ For the label-based biosensors, SERS signals are from extrinsic Raman reporters or molecules with higher sensitivity. SERS tags can be composed of metal elements modified by target recognition elements (antibodies, peptides, aptamers) and Raman reporting molecules (4-ATP, 4-MBA). An antibody-conjugated GO@Au nanosheet was introduced into the immunochromatographic assay (ICA) system as a SERS label. By rapidly and effectively adhering to the bacterial surface, GO@Au increases the dispersion of bacterial-nanogold complexes on ICA strips, providing many stable hot spots for SERS signal enhancement, thus enabling efficient and sensitive detection of pathogenic bacteria.⁶⁸ As one of the most classical detection methods, “Sandwich-type” assay can be combined with SERS technology to detect pathogens. GO-Au nanostars decorated with Raman reporters and aptamers can be used as an SERS tag, which can capture E. coli and S. aureus by an aptamer probe and then combine with SERS tags to form a sandwich-like structure, resulting in an enhanced electromagnetic field due to the dual enhancement strategy, thus enabling the detection of bacteria.⁷⁰

Electrochemical sensors

Electrochemical biosensors are a kind of analytical device composed of target recognition element, signal transduction element, and electrochemical signal output element, which can convert biochemical reaction energy into measurable electrical signals. Electrochemical sensors based on nanomaterials can provide a suitable microenvironment for the immobilization of biomolecules, thereby promoting the electron transfer between the immobilized biomolecules and electrodes. Therefore, compared to the traditional method, it has the advantages of high sensitivity and fast response time. Depending on the type of chemical response, electrochemical biosensors can be classified into amperometric, voltammetric, potentiometric, and impedimetric biosensors.

The impedance-based method evaluates the resistance of electron transfer to the electrode by a Nyquist plot; amperometric/voltammetric-based methods measure currents by gauging constant/variable potentials in the process. As for potentiometric-based methods, there are no stream flows across indicating the electrodes and analytes, output signals are generated primarily by the accumulation of ions around the electrode based mainly on an ion-sensitive field effect transistor or ion-selective electrode. AuNPs−DNA/H37Rv aptamer/MSPQC sensor uses H37Rv aptamer as the recognition probe, a multichannel series piezoelectric quartz crystal system as s ion-electron potentiometric transducer and aptamers to detect the change in frequency shift. Thus, Mycobacterium tuberculosis are detected accurately and rapidly.⁷⁷ Different analytical methods can be combined to improve the accuracy of bacterial detection. For example, composition films of AuNPs/MOFs conjugated with a DNA aptamer have good electrical conductivity and enhanced electron transfer properties. In the supernatant of the device, the electrochemical signal in the test solution increased due to the S. aureus-specific micrococcal nuclease cutting off the DNA aptamer on the electrode surface. Additionally, at the DNA/AuNPs/MOF-sensing interface, the electrochemical signal in the test solution is reduced because S. aureus accumulates on the electrode surface, resulting in higher interfacial impedance.⁷⁸

POCT devices

Point-of-care (POC), also called bedside diagnosis, can reduce the complexity of traditional testing operations and has the advantages of simplicity and speed. The POCT device consists of a sensing system and a readout system: nanomaterials can be used as an outstanding sensing system to detect microorganisms, and simple eyes and/or a smartphone application can be used as a readout system to obtain accurate results (Figure 3).

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By combining traditional detection methods, such as polymerase chain reaction (PCR) and agglutination reaction with nanomaterials, bacteria can be detected quickly and conveniently. For instance, photonic PCR is a reliable diagnostic tool for rapid POCT, which utilizes photothermal nanomaterials as heating elements to reduce the power consumption of the reaction and improve the photothermal conversion.⁷⁹ Lectin-functionalized chitosan nanoparticles can be entrapped by crystal violet, resulting in macroscopic aggregates that can be used to detect clinical bacterial infections.⁵⁰

Microfluidic technology integrates various types of units in a chip, and their small analysis platform, short detection time, and low sample consumption make them widely used in various bacterial detection. A chip with nanomaterials has improved the performance of the detection. There is a nanoporous membrane combined with the chip, which can achieve gravity-driven cell enrichment, drive photothermal lysis, and perform ultrafast photonic PCR to identify E. coli.⁸⁰ In addition, a centrifugal microfluidic automatic wireless endpoint detection system integrated with loop-mediated isothermal amplification is developed for the detection of different pathogenic bacteria. The presentation of the final result was detected by Calcein dye colorimetry, and the color change of the dye was transmitted to a smartphone to analyze the presence of pathogenic bacteria.⁸¹

Machine learning-assisted sensor arrays

Different from the traditional sensor system consisting of a single probe and an analyte, the array sensor uses multiple sensor units to form an array. Through the cross-response between the sensor array and the analyte, the array sensor can detect or respond to various substances and complex mixtures. At the same time, the experimental data can be further analyzed by machine learning algorithms.

AuNCs modified by proteins respond to specific bacteria, which leads to the fluorescence intensity of protein-AuNCs in the supernatant changing to corresponding degrees, resulting in a unique finger pattern to distinguish and classify different types of bacteria. Consequently, four protein-encapsulated AuNCs are used as fluorescent array sensors for rapid bacterial identification.⁸² In addition, array sensors can discriminate multiple bacteria by different responses to the probe. Because bacteria have different metabolic capacities for different d-amino acid (D-AA), a colorimetric sensor array for bacteria fingerprinting using D-AA-modified AuNPs as probes is constructed, which shows good quantitative analysis of individual bacteria and differentiation ability of bacterial mixtures by learning response patterns.⁸³ Recently, dual-mode sensor arrays have also been designed to identify multiple pathogens, which show better accuracy and convenience. A colorimetric and photothermal dual-mode sensor array based on boronic acid-functionalized Au−Fe₃O₄ nanoparticles (BA–GMNPs) is used to differentiate multiple pathogenic bacteria. Because different BA−GMNPs@bacterial complexes differed in resisting assembly and producing different colorimetric and photothermal response signals, the unique molecular fingerprint of each bacterium can be obtained through the linear discriminant analysis of the response pattern.⁸⁴

NANOMATERIALS AND ANTIMICROBIAL TREATMENT

Nano-based targeted therapy

Targeted therapy using nanomaterials as drug carriers has better antimicrobial effects than free drugs. Some nanomaterials are commonly used for targeted therapy, including liposomes, polymeric nanoparticles, extracellular vesicles, silicon-based nanomaterials, CNMs, metal-based nanomaterials, and so on.

Liposomes

Liposomes are vesicles with a lipid bilayer structure. Because of their early discovery and excellent drug delivery performance, liposomes have become the primary choice of the most successful nanocarriers. Several liposome formulations of antimicrobial agents have been approved for use or tested in clinical trials by FDA.⁸⁵ With the protection of liposomes, drugs can be safely transported to specific sites and released in a controlled manner. Therefore, drugs combined with liposomes have improved antibacterial activity, lower toxicity, and side effects, less loss in transportation, and lasting effects.⁸⁶ Comparing the efficacy of levofloxacin combined with different vectors against Pseudomonas aeruginosa, anionic liposomes enabled the drug transport through artificial mucus, maintained levofloxacin's antibacterial effect, and remained low cytotoxicity even at high doses. Moreover, the anionic liposomes could continuously release the drug for 72 h, achieving a sustained antibacterial effect.⁸⁷ However, due to the lack of specificity, the accuracy of drug delivery using simple liposomes is still limited. Therefore, researchers tend to modify the liposome, including surface modification,^88,89 protein corona regulation,⁹⁰ and so on.

Polymeric nanoparticles (PNs)

PNs have been favored by researchers due to their stability and various functional groups that can be modified.⁹¹ Among them, chitosan-based NPs and poly (lactic-co-glycolic acid) (PLGA) NPs are among the most frequently used PNs as drug carriers.⁹²

For chitosan, the amino group on the main chain gives it multicationic properties that facilitate the encapsulation of drugs. Various active functional groups make it easy to modify and endow it with better drug stability, controllable drug release, and so on.^93–95 However, some formulas of chitosan-based nanocarriers still have defects, such as cytotoxicity. Chitosan hydrogel film is prepared by using glutaraldehyde as a crosslinking agent, which is cytotoxic. Some researchers have used photo-crosslinking technology to solve the problem.^96,97

PLGA NPs are biodegradable polymers approved for drug delivery by the FDA due to their biocompatibility.^98,99 PLGA NPs have been used to deliver chemical drugs such as curcumin (CUR)¹⁰⁰ and furanone C-30¹⁰¹ to improve their effects, but have also been applied to solve some shortcomings of therapeutic application of peptides. BAR, a peptide from Streptococcus gordonii, can prevent the formation of biofilms but has the defect of requiring a higher concentration to inhibit the generated biofilms and having a short action time. BAR-modified PLGA NPs enhance multivalent association with Porphyromonas gingivalis, increase the concentration of BAR at the action site and achieve better antibiofilm effect compared with free BAR.^102,103 BAR-encapsulated PLGA NPs enable BAR to be released slowly, thus extending the action time.¹⁰⁴ Moreover, AMPs are also limited by their instability in vivo, which can be addressed by developing AMP-loaded PLGA NPs.^105,106 Moreover, AMP-grafted PLGA-PEG NPs have been proven to facilitate better AMP exposure and targeting, unlike AMP-loaded NPs, which rely on release profiles.¹⁰⁷

For the treatment of intracellular bacterial infections, macrophages could rapidly take up PLGA NPs carrying active molecules at low doses without cytotoxicity, suggesting that PLGA NPs can be a promising vector for the treatment of intracellular bacterial infections.¹⁰⁸ Moreover, PLGA NPs that have been modified may achieve better results. PLGA−lipid hybrid microparticles loaded with rifampicin were more easily phagocytized by macrophages and had a stronger ability to release rifampicin compared with PLGA NPs.¹⁰⁹ PLGA NPs and ultrasound were combined to promote macrophage phagocytosis of NPs, ROS production and macrophage apoptosis.¹¹⁰

Extracellular vesicles (EVs)

EVs are a kind of membranous vesicles produced by cells, thus having high biocompatibility, better stability, and the ability to cross the blood–brain barrier (BBB).¹¹¹ Exosomes, a commonly used EV, was used to deliver linezolid, achieving a better antibacterial effect with no cytotoxicity on macrophage MRSA intracellular infection than free drugs.¹¹² However, due to the cell source, the efficiency, quality, and cost of mass production of EVs is a major challenge to be overcome in clinical translation.

Silicon-based nanomaterials

Silicon-based nanoparticles can efficiently deliver drugs and are easily modified. Among silicon-based nanoparticles, porous silicon (PSi) is commonly used due to its controllable drug release, originating from its adjustable pore structure, and its ability to degrade under special conditions such as ROS.^113–116 Moreover, PSi has a solid ability to deliver drugs consistently. Triclosan-loaded PSi sustained antibacterial effects for more than 100 days and improved the solubility of triclosan for the first 15 days.¹¹⁶ PSi has also been modified to obtain many other unique properties. Surface modification of PSi with polydopamine results in more functional groups on the surface of the material, giving it the ability to produce photothermal effects.¹¹⁷

CNMs

Due to their unique structural characteristics, carbon nanocarriers can generally improve the stability of drugs, reduce the drug dose required for treatment, prolong the drug action time, and so on. For example, MDC@MCNs can resist the degradation of trypsin, are more easily absorbed by cells than free drugs, and stay in the gut longer, thus enhancing the efficacy of MDC.¹¹⁸ GO sheet with surface modification of APDMH slowed the release of oxidative chlorine −5.35% of the total amount released in 30 min.¹¹⁹ Moreover, by binding the mesoporous Fe₃O₄ Nanospheres to carbon nanotubes, they become better agents for microwave therapy (MCT) to target and eradicate deep infections.¹²⁰

Metal-based nanomaterials

Metal-based nanomaterials, like other drug carriers, can reduce the toxicity of drugs, but due to their bactericidal properties, they can cooperate with drugs to kill bacteria, especially drug-resistant bacteria.¹²¹ Moreover, metal-based NPs can be classified as photothermal agents, which help kill bacteria while delivering drugs. AuNSs@Van itself can target and kill bacteria, resulting in the elimination of 81% of the bacteria. This proportion can be further reduced to less than 1% through the photothermal effect generated by AuNSs.¹²²

Nanovaccines

In developing vaccines, nanomaterials can be used as vaccine vectors and adjuvants. Similar to drug vectors, nanomaterials can protect antibodies (or drugs) and release them controllable to obtain long-lasting immune responses. Meanwhile, nanomaterials have been proven to be a promising adjuvant, which can effectively improve the immunogenicity of antibodies and promote the immune response.¹²³ Some NPs even induce a stronger immune response than conventional adjuvants.¹²⁴ Moreover, compared with traditional adjuvants, nanomaterials avoid the systemic distribution of adjuvants and reduce the required dose of antibodies, thus achieving low cytotoxicity (Figure 4).¹²⁵ Based on the above characteristics, nanomaterials are often used to solve the shortcomings of existing antibacterial vaccines in recent years, such as TB, anthrax, cholera, whooping cough, and so on.

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Bacille Calmette Guérin (BCG), the only vaccine approved for TB, is effective for neonates, but the immune induction effect decreases with age. Comparing encapsulating the H1 antigen that includes antigens Ag85B and ESAT-6 to PLGA NPs with the vaccination of H1 antigen alone, NPs released the antigen within a few weeks, enhanced phagocytosis of macrophages and induced a more intense immune response including the increased concentration of IgG and enhanced release of cytokines, which resulted in a significantly reduced bacterial load in lung and spleen.¹²⁶ However, the H1 antigen-encapsulated liposomes with PolyIC adjuvants showed that the Th1/Th17-Th2 immune response to Ag85B was induced while the immune response to ESAT-6 was weak.¹²⁷ These results suggest that although NPs enhance the effectiveness of TB vaccines, the ability to induce cellular immunity may still need to be improved. Except for effectiveness, a mucosal TB vaccine that could reduce the release of harmful inflammatory mediators through unconventional IRF-3-related signature-mediated antigen presentation has been proven to improve the safety of the vaccine.¹²⁸

BioThrax (anthrax vaccine adsorbed [AVA]) was the only vaccine approved by the FDA for anthracnose, but it was not widely used because it required multiple vaccinations over a short period to strengthen the immune protection and it only targeted a later stage of infection. FUC-TMC NPs combined with AVA could be well taken up by DCs and produce a stronger immune response with 100% protection against spore attack. Meanwhile, FUC-TMC NPs were more cost-effective than CpG ODNs, an emerging vaccine adjuvant.¹²⁹ Attaching spores and toxin proteins of Bacillus anthracis to nanolipoprotein particles containing the Toll-like receptor 4 agonist monophosphoryl lipid A. could produce continuous antibody titers by single vaccination and faster immune response with multiple vaccinations.¹³⁰

Nanomaterials also provide fresh ideas for developing some new antibacterial vaccines, especially subunit vaccines, intranasal vaccines, and so on. Subunit vaccines composed of the components of microorganisms (peptides, toxins, etc.) have solved the safety problems of traditional live vaccines, especially for immunocompromised populations, while they have poor immunogenicity, which nanomaterials can solve as adjuvants. The development of intranasal vaccines is limited by the mucosal barrier of the nasal cavity, and nanogels made from cholesteryl-group-bearing pullulan (cCHP) have been proven to be excellent carriers, which can adhere to the negatively charged nasal mucosal surface, thus prolonging the action time.^131,132 Although cCHP itself does not promote antigen presentation, it can induce a stronger immune response due to its ability to reduce the influence of mucosal barriers on antigens.¹³³

Nano-based phototherapy

Due to their unique optical properties, nanomaterials are applied to photosensitizers in phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT). PDT is a treatment that kills bacteria through ROS produced by photodynamic agents (PDAs) that transfer energy to oxygen under laser light. Similar to PDT, PTT is a treatment that allows photothermal agents (PTAs) to convert light energy into heat energy to eliminate bacteria.^134,135 Compared to traditional antibacterial treatments, phototherapy is a light-activated, precise and antibiotic-free antibacterial strategy, thus endowing it with a broad antibacterial spectrum, high selectivity, and low bacterial resistance. APTMS@SPIONs were developed as both PTAs and PDAs, effectively destroying bacteria and biofilms under 808 nm laser irradiation. However, APTMS@SPION/laser showed strong killing effects only on P. aeruginosa and E. coli but weak on Klebsiella pneumonia and Staphylococcus epidermidis. Moreover, the effectiveness of PTT and PDT against different bacterial biofilms varied. These suggest that there are still limitations that need to be addressed in phototherapy.¹³⁶

Fortunately, the disadvantages of phototherapy, such as poor effect on some bacteria and damage to healthy tissues caused by the high temperature of the photothermal effect, can be counteracted by combined treatment. Combining phototherapy with targeted therapies is a promising way to improve efficacy and reduce side effects. It is mainly combined with bacterial infectious microenvironment (BIME) response, Van targeting, and antigen-antibody targeting.

Vancomycin is a glycopeptide antibiotic with a high affinity for a dipeptide (d-alanyl-d-alanine) at the bacterial wall. Through the modification of Van-OA, Van-OA@PPy NPs have been proven to adhere to MRSA more easily and adequately, resulting in significant membrane damage of MRSA after 808 nm laser irradiation.¹³⁷ When the species of the bacteria responsible for the infection is known, the combination of antigens and antibodies can be used to target the bacteria, which is more specific. A molecularly imprinted nanocarrier loaded with the photosensitizer (methylene blue) bound to bacteria specifically through LPS and had better antibacterial effects after laser irradiation.¹³⁸

BIME response is to capture the bacteria through the particular environment created by bacteria at the site of infection, including the electrical properties of bacterial membranes and the changes in pH, enzyme expression, oxygen content, and temperature, thus making PTT and PDT easier to work with. It is worth noticing that BIME response has a solid effect on eliminating biofilms. A novel core-shell nanocomposite improves biofilm penetration through electrostatic interactions with bacteria resulting from the protonation of MAA in an acidic infection microenvironment and volume shrinkage after NIR irradiation.¹³⁹

For eliminating biofilms, using DNase to decompose extracellular polymeric substance matrix and expose bacteria improves the efficacy of phototherapy and is also one of the effective ways to eliminate biofilms.¹⁴⁰ In addition, AuNRs functionalized with pLAMA and pFEMA inhibit the adhesion and biofilm formation by competitively binding to LecA and LecB lectins and eliminate drug-resistant P. aeruginosa by photothermal effects of AuNRs.¹⁴¹

The combination of phototherapy and chemotherapy can not only improve the antibacterial effect due to the addition of substances with antibacterial function, but also have some special interactions, such as controlling the release of drugs, reducing the loss of drugs, synergistic antibacterial effect, and so on. Regarding chemical species, phototherapy is often combined with antibiotics and NPs with antibacterial properties. As AuNPs are promising PTAs and both AgNPs and AuNPs have natural antibacterial properties, an AuAgCu₂O nanoshell was developed, which not only generates heat but also continuously releases Ag ions after exposure to NIR, achieving a dual antibacterial effect.¹⁴² Moreover, AgNPs alone have poor antimicrobial efficacy in the presence of biofilms due to their insufficient ability to penetrate biofilms, while Ag-AuNPs can produce photothermal effects to damage biofilm, which enables AgNPs to penetrate the biofilms, kill bacteria, and prevent bacterial regeneration.¹⁴³ For combining with antibiotics, Bi₂S₃−S-nitrosothiol−acetylcholine (BSNA), a NIR photosensitive, reduced bacterial resistance to antibiotics through inhibiting glucose metabolism in bacteria, which helped solve one of the biggest weaknesses of tetracycline-class antibiotics.¹⁴⁴ Recently, some researchers encapsulated the photosensitizer (AIE-PEG₁₀₀₀ NPs), teicoplanin (Tei) and ammonium bicarbonate (AB) in lipid nanovesicles. After exposure to NIR, AIE-Tei@AB NVs produce photothermal and photodynamic effects, which make AB decompose into CO₂/NH₃ bubbles, NVs collapse, and Tie release rapidly. These reduce the plasma binding rate of Tie and improve the antibacterial effect.¹⁴⁵

In addition, phototherapy can be combined with gas therapy. NO can directly eliminate bacteria by damaging DNA and disrupting the protein function to reduce the temperature required to achieve the ideal bactericidal effect, thereby reducing damage to healthy tissues. Moreover, NO can react with ROS to form the reactive nitrogen species (RNS), thus enhancing PDT's efficiency.¹⁴⁶ CO is capable of inducing host immune response, inhibiting bacterial cell respiration, and eradicating biofilm, while it has high requirements for targeted delivery and precise release due to its high affinity with hemoglobin.^147,148 A synergistic antibacterial and antibiofilm system based on PDT and CO (Ce6&CO@FADP) was highly permeable to bacterial membranes due to the fluorination effect and produced CO rapidly in bacteria without affecting ROS production.¹⁴⁹

Since the efficiency of PDT depends on ROS production, hypoxia in infected tissues may limit the efficacy of PDT. rGO/CuO₂, an oxygen self-supplying PDT platform, took CuO₂ as the oxygen source and used rGO to trap electrons and produce ROS, thus eliminating MRSA by interrupting the respiratory chain and PDT.¹⁵⁰ It is worth noting that another major shortcoming of PDT is that the light used to activate the photosensitizer is mainly from the UV-vis region and is not sufficient to penetrate deep tissue. To conquer the obstacle, developing longer-wavelength absorbing photosensitizers is a commonly-used way and NIR-absorbing photosensitizers have been proven to be a good alternative due to NIR's strong penetration ability and less absorption by tissues.¹⁵¹ In addition, combining PDT with targeted therapy or delivering PDAs to the site of infection through the nano-based drug delivery system can also increase its accumulation in deep tissues.^152,153 Moreover, the combination with the delivery system can also avoid the disadvantages of high hydrophobicity of most PDAs, thus improving the antibacterial performance of PDT.¹⁵⁴

APPLICATIONS OF NANOMATERIALS IN DIFFERENT INFECTIOUS DISEASES

Nanomaterials have been widely applied in the treatment of various infectious diseases as described below (Figure 5 and Table 2).

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Table 2 Advances in the development of NPs to treat bacterial infectious diseases.

Treatment	Disease	Targeted microorganism	Nanomaterial	Function	Ref.
Respiratory infections
Drugs	Pneumonia	Klebsiella pneumonia	Calcium phosphate nanorods	Reduce drug resistance	[155]
Acinetobacter baumannii	Au-Ag hybrid nanocage	Destroy MDR bacteria, promote lung repair	[156]
Pseudomonas aeruginosa	ICG-loaded nanoplatform	BIME-activated PTT and PDT	[157]
Intracellular infection	MRSA	MOF ZIF-8	Phagocytose through CD44 to eradicate MRSA	[158]
Tuberculosis	Mycobacterium tuberculosis	INH and RMP-loaded nanogel particles	Sustained drug release, lung targeting, lower cytotoxicity	[159]
Vaccine	Pneumonia	MDR A. baumannii	Chitosan-PLGA-rOmp22 NPs	More specific IgG, IFN-γ, effective protection	[160]
Streptococcus pneumoniae	Ag@AuNPs	Th1/Th2 immune responses sand opsonization	[161]
Pneumonic plague	Yersinia pestis	Polyanhydride NPs	Rapid immune response and long-term protection	[162]
Tuberculosis	M. tuberculosis	PEG-PPS	Stronger CD1b-restricted T cell responses	[159]
Diagnosis	/	Enterococcus faecium	AuNPs	Rapid and portable diagnosis	[163]
/	Legionella pneumophila	AuNPs	Faster and simpler diagnosis	[164]
Tuberculosis	M. tuberculosis	Glycan-functionalized magnetic NPs	Biosafety, high efficiency, low cost	[165]
Respiratory tract infections	/	SERS nanotags	Ultra-sensitive, high throughput	[166]
Immunotherapy	Excessive immune response	/	Fusogenic porous silicon NPs	Silence Irf5 genes	[167]
Skin and soft tissue infections
Wound dressing	Wound infections	MRSA	Au/perlite/chitosan ointment	Reduce bacterial colonization, accelerate wound healing	[168]
Escherichia coli, Staphylococcus aureus	Curdlan hydrogels	Inhibit bacteria growth, reduce inflammation, support fibroblasts' attachment	[169]
Skin infections	MRSA	PLGA microspheres	Inhibit efflux pumps, continuously release drugs	[170]
Acute skin injuries	S. aureus, Staphylococcus epidermidis	Chitosan hydrogel	Faster drug release	[171]
Tissue healing	/	/	Poly (aspartic acid)	Eliminate infection, promote fibroblast proliferation	[172]
Drugs	Skin and implanted catheter infections	Cutibacterium acnes	Cationic liposomes	Better targeting and penetration to remove bacteria and biofilms	[173]
Wound infection	S. aureus	Ultra-thin hollow silica NPs	pH response release, better PDT, wound healing	[174]
Intracellular bacterial infection	S. aureus	HA-cholesterol nanohydrogels	Deliver drugs into cell lysosomes	[175]
Vaccine	/	S. aureus	Magnetic mesoporous silica NPs	Promote antigen presentation by DCs	[176]
Diagnosis	/	/	Fe3O4@C NPs	Visual diagnosis, on-site disinfection	[177]
Central nervous system infections
Drugs	Brain infections	/	CG3R6TAT NPs	Have broad-spectrum antimicrobial activity and cross the BBB possibly by adsorptive endocytosis	[178]
Pneumococcal meningitis	S. pneumonia	RVG29-Nano-BAP85	Cross the BBB by receptor-mediated endocytosis	[179]
Vaccine	/	E. coli K1	Chitosan-modified PLGA NPs	Deliver Vo, induce the same humoral immune response as Al(OH)₃	[180]
Bone infections
Therapeutic material	Bone defects	S. aureus	Gellan gum-based hydrogel with nHA/CHX	Remove bacteria and biofilm, promote osteogenesis	[181]
Implanted material	Bone defects	/	AHRG scaffolds	Inhibit biofilm formation, promote osteogenesis	[182]
Implant infections	/	LBL@MSN-Ag NPs	Inhibit infections, promote new bone formation	[183]
Drugs	Osteomyelitis	MRSA	Au/TNT@PG	Efficient bacterial capture, biofilm penetration, sonodynamic catalysis	[184]
Urinary tract infections
Drugs	Urinary tract infections	E. coli	Mesoporous silica NPs	Swim on biofuels, kill bacteria by enzymatic products of urease	[185]
Serratia marcescens	Chitosan-g-PMDA-CYS conjugated to AuNPs	Controlled drug release, reduced drug resistance	[186]
Diagnosis	/	E. coli	PAC-polyaniline NCs	Sensitive, reproducible, stable and specific detection	[187]
/	P. aeruginosa	ZnO-Cys	Detect P. aeruginosa by AHLs, have high sensitivity	[188]
/	/	AuNPs	Rapid and accurate identification	[189]
Gastrointestinal infections
Drugs	Gastric infections	Helicobacter pylori	Chitosan/poly (acrylic acid) particles	Increase gastric retention time, decrease amoxicillin dose	[190]
Intestinal infections	Shigella	Calcium-phosphate NPs	Reduce bacterial drug resistance	[191]
Vaccines	/	H. pylori	HP55/PLGA NPs	Controlled release, effective induction of immune response	[192]
Other infections
Drugs	Otitis media	S. aureus	CUR/TSIIA/chitosan NCs	Ideal antibacterial effect without inducing drug-resistance	[193]
Periodontitis	/	Fe2O3-modified 2D porphyrinic metal-organic framework	Broad antimicrobial spectrum based on photodynamic effects	[194]
Recurrent periodontitis	Porphyromonas gingivalis	PMPC and PDPA block co-polymers	Eliminate intracellular bacteria, prevent recurrence	[195]
Ocular bacterial infections	/	EtNBSS NPs	Mild photothermal effects	[196]
Diagnosis	Corneal ulcers	P. aeruginosa	AuNPs	Rapid and specific diagnosis	[197]

Respiratory infections

Due to the diversity of drug-resistant bacteria, respiratory infections are often difficult to eradicate, resulting in long-term infections and eventually severe, irreversible tissue damage. Nanomaterials are regarded as an effective means to combat these drug-resistant bacteria, including P. aeruginosa, Acinetobacter baumannii, MRSA, and K. pneumonia, through eliminating factors associated with the development of drug resistance.¹⁹⁸ Under the premise that the pH of drug release and alginate lyase catalytic activity is similar to that of the niche of the P. aeruginosa biofilm, the silver nanocomposite penetrates the biofilms with the help of alginate lyase and releases AgNPs and ceftazidime to eliminate P. aeruginosa from the mice lungs.¹⁹⁹ AMP IK8L has been identified to inhibit K. pneumoniae biofilm through the STAT3/JAK signaling and regulate inflammatory cytokines to reduce lung injury and eliminate the bacteria in mice.²⁰⁰ Tigecycline-loaded, TPGS-modified and Ts peptide-functionalized nanorods inhibit the efflux pumps of MDR K. pneumonia through TPGS, deliver Tigecycline to bacteria through the targeting ability of Ts peptide and consequently raise the survival rate of mice with pneumonia.¹⁵⁵ A Van-loaded HA-modified framework material ZIF-8 can be phagocytosed by macrophages through binding to the CD44 receptor and disintegrate in lysosomes to eliminate intracellular MRSA.¹⁵⁸

Recently, a microrobot was constructed by attaching antibiotic-loaded neutrophil membrane-coated PNs to natural microalgae. Active targeting to infection sites by the motility of microalgae enables the microrobots to be evenly distributed in deep lung tissue, less cleared by macrophages, and to stay longer. Besides, the microrobot effectively reduces the bacterial burden at the site of infection and avoids excessive immune response through the neutrophil membrane. These make it a promising way to cure ventilator-associated pneumonia.²⁰¹

Nanomaterials can also be applied in disease diagnosis, vaccine development and immunotherapy. The combination of GMNP and Tween 80 improves the count of acid-fast bacilli, thus providing a simpler, faster and cheaper method for detecting TB.¹⁶⁵ For vaccine development, in addition to anthrax and TB vaccines mentioned above, NPs have also been used to develop vaccines against common pathogens such as Streptococcus pneumoniae,¹⁶¹ A. baumannii,¹⁶⁰ Yersinia pestis,¹⁶² and so on. For immunotherapy, since the excessive immune response may hinder the repair of lung tissue, siRNA-loaded pSiNPs were developed to silence the Irf5 gene in macrophages by RNAi, thereby preventing the excessive inflammatory response.¹⁶⁷

Skin and soft tissue infections

NPs can be involved in the development of new antibacterial agents to combat some common pathogens of skin and soft tissue infections, such as S. aureus, Cutibacterium acnes, and so on. Ce6-loaded chitosan-modified UHSN increased ROS production due to the interaction between UHSN@CS and Ce6, which resulted in the elimination of S. aureus and its biofilms and the promotion of wound regeneration.¹⁷⁴ In addition, Mel-loaded NISV had good transdermal properties and effectively inhibited the growth of drug-resistant S. aureus.²⁰² Furthermore, DNase I and PK-loaded cationic liposomes can inhibit C. acnes and its biofilm both in skin and catheters, and down-regulate biofilm-related virulence genes.¹⁷³

Developing novel wound dressings that isolate the wounds from the external environment, kill bacteria, and heal wounds is often dependent on nanomaterials. Curdlan hydrogel embedded with AgNPs, with favorable mechanical properties, not only effectively kills E. coli and S. aureus, but also promotes the attachment and growth of fibroblasts to accelerate wound healing and down-regulate the expression of inflammatory genes stimulated by LPS.¹⁶⁹ A novel chitosan-based hydrogel can rapidly release drugs in response to acute skin injury.¹⁷¹ Moreover, promising skin defect therapy materials often possess anti-infective and tissue-healing properties. A multifunctional nanodelivery system is capable of delivering plasmid encoding EGF (pEGF) with good transfection performance, and the addition of tobramycin provides antibacterial properties.¹⁷²

In terms of microbial diagnosis, a photonic hydrogel platform can achieve both visual diagnosis and photothermal disinfection: the gel color changes according to the pH of BIME, and the pathogen was removed by photothermal effect after NIR irradiation.¹⁷⁷ However, such a method is more suitable for rapid diagnosis in the early stage of infection, and more specific detection methods should be carried out to further identify the pathogen species. In the sphere of vaccine research, a multi-antigenic vaccine (EV/ICG/MSN) against S. aureus promotes antigen presentation by DCs and is safely delivered to lymph nodes to induce cellular immune responses. In the skin infection experiment, the nanovaccine has shown an excellent ability to prevent and treat superficial and even systemic infections.¹⁷⁶

Central nervous system infections

The obstacle to treating central nervous system infections is the BBB, which is highly selective for passing substances. Therefore, the insufficient drug concentration caused by the difficulty for antibiotics to cross the BBB and the resistance of bacteria make central nervous system infections more difficult to solve. Under these circumstances, using nano-drug carriers across the BBB or implementing antibiotic-free strategies provide new ideas for the treatment.

CG₃R₆TAT NPs, formed by self-assembly of TAT peptide, not only have broad-spectrum antibacterial activity, but also can cross the BBB, possibly through adsorptive endocytosis.¹⁷⁸ A micellar system, using the RVG₂₉ ligand as brain targeting ligand and Pluronic® P85 unimers to improve membrane translocation, could efficiently cross the BBB through receptor-mediated endocytosis and have an excellent therapeutic effect on drug-resistant pneumococcal meningitis with no cytotoxicity.¹⁷⁹ In addition, chitosan-modified PLGA NPs can deliver recombinant protein OmpAVac to prevent E. coli K1. However, whether this delivery mode is effective remains to be confirmed due to the lack of an experiment evaluating the ability of VoNPs to induce immune responses in E. coli K1 meningitis model.¹⁸⁰

Bone infections

Osteomyelitis is a devastating bone disease often treated by intravenous injection of high-dose antibiotics, surgery, and so on. However, high doses of antibiotics may easily lead to bacterial drug resistance, which hinders the treatment of osteomyelitis. A BIME-activated nanoplatform (Au/TNT@PG) penetrated biofilms through positively charged PG and exerted sonodynamic effects, thus eliminating MRSA biofilms, inhibiting inflammation, and promoting osteogenesis. The superior tissue penetrability of ultrasound makes it promising to treat deep bone infections.¹⁸⁴ In addition to sonodynamic-catalytic therapy, MCT can be used to treat deep bone infections either due to its superior penetrability.^120,203

In recent years, antibiotic-impregnated scaffolds have been widely applied to treating osteomyelitis because they can effectively increase the local antibiotic concentration. A Van-loaded nanocomposite fibrous scaffold can sustain Van release for up to 30 days to inhibit MRSA growth. Meanwhile, the nanoscaffolds provided good structural support for osteogenesis, while commercial materials, such as Stimulan, do not have such properties due to their rapid degradation.²⁰⁴

Except for osteomyelitis, NPs have been applied to implant infections. A multifunctional nanoplatform (LBL@MSN-Ag) can be degraded by glutamyl endonuclease and release AgNPs. Ti implants combined with LBL@MSN-Ag have been shown to be effective in inhibiting bacterial growth and promoting new bone formation.¹⁸³ In addition, an NTATi-G implant has been proven to have better biocompatibility compared to the conventional gentamicin-loaded Ti implant.²⁰⁵

Urinary tract infections

E. coli is a common pathogen of urinary tract infections. Urease-functionalized mesoporous silica NPs can swim using urea as a biofuel and eliminate uropathogenic E. coli by the enzymatic products of urease. Moreover, U-MSNPs reduce the biofilm by 60% at a concentration of more than 200 μg/mL.¹⁸⁵ Serratia marcescens is also a pathogen for urinary tract infections and nosocomial infections. A polymer-based system (AuNPs/RF/INH/CS-g-PMDA-CYS system) to deliver drugs against nosocomial S. marcescens reduced bacterial drug resistance by inhibiting swarming motility and prodigiosin pigment production, and improved the survival of Caenorhabditis elegans by inhibiting biofilm and virulence.¹⁸⁶

Diagnosis of urethral pathogens, such as urine culture, is time-consuming and laborious, while alternative strategies, such as PCR and ELISA, need professional persons and instruments. As a result, researchers made nanobiosensors that specifically detect E. coli through the agglutination reaction of cranberry proanthocyanidins²⁰⁶ and tailored E. coli receptors.²⁰⁷ A photoluminescence-based biosensor using ZnONPs diagnoses P. aeruginosa by AHLs, a signaling molecule secreted by itself, and has high sensitivity even in the presence of interferences.¹⁸⁸ Unlike the diagnosis of a single pathogen described above, a novel sensor consisting of amino-modified AuNPs and six DNAs signal molecules achieved rapid and accurate identification of five major urinary tract pathogens.¹⁸⁹

Gastrointestinal infections

The high acidic environment in the stomach is an essential part of the digestive process, but it is a huge obstacle to treating gastric infections. Helicobacter pylori is one of the most troubling gastric pathogens, and clarithromycin, metronidazole, and amoxicillin are the first-line drugs. However, clarithromycin and metronidazole have high drug-resistance rates, and amoxicillin is not stable in the complex gastric environment, resulting in the need for high doses and severe adverse reactions. SPIO/AMO@PAA/CHI carrying amoxicillin can adhere to and rapidly cross the gastric mucosa with the help of chitosan and facilitate the release of amoxicillin by PAA, which competes with amoxicillin for binding to chitosan. These ultimately lead to a reduction in the doses required for treatment.¹⁹⁰ Besides, an amoxicillin nanosphere released the drug for up to 12 h, allowing for sustained antibacterial activity.²⁰⁸ Developing nonantibiotic strategies is also an effective means to solve the existing dilemmas. MSI-78A grafted SAMs adsorbed H. pylori to the surface and killed 98% of H. pylori in just 2 h, suggesting that these AMP-grafted NPs might be a promising therapeutic option.²⁰⁹ Although grafting improves the stability of AMP in vivo, it remains to be seen whether the NPs can resist the complex environment of the stomach and achieve good therapeutic effects.

Among intestinal infections, Shigella is a common pathogen that causes bacterial dysentery, resulting in many infections and deaths. Furthermore, Shigella is prone to become multidrug resistant strains, further aggravating the difficulty of treatment. The application of NPs brings hope for treating Shigella, including solving the existing antibiotic resistance and developing antibiotic-free treatment. Due to the high membrane-penetration property, tetracycline-encapsulated calcium-phosphate NPs address drug resistance arising from the block of tetracycline entry into bacteria.¹⁹¹ Polyamidoamine dendrimer glucosamine, as a nonantibiotic drug, has been proven to reduce bacterial invasion and intestinal tissue damage in a rabbit model of shigellosis.²¹⁰

Another problem to be solved in intestinal infections is the disturbance of normal intestinal flora caused by antimicrobial therapy, especially broad-spectrum antibiotics. Therefore, the effects of drugs on normal flora must be considered in developing new antibacterial agents. DAPT-coated AuNPs have better antibacterial effects than levofloxacin and have no harm to normal intestinal flora.²¹¹

Except for antibacterial agents, NPs have also been applied to disease diagnosis and the development of vaccines. Electrochemical immunosensor based on carbon nanotubes, chitosan and GO have greater sensitivity and selectivity for detecting Clostridium difficile toxin B.²¹² Researchers have developed HP55/Poly(n-butylcyanoacrylate) (PBCA) NPs and HP55/PLGA NPs as carriers for oral H. pylori subunit vaccines capable of protecting the contents from the complex environment and inducing effective immune protection.^192,213

Other infections

The treatment of otitis media also faces the challenge of drug resistance. Antibacterial components (CUR, Tanshinone IIA, chitosan) loaded NPs combined with sonodynamic therapy not only exhibit bactericidal activity similar to ofloxacin, but also don't induce drug resistance.¹⁹³ Silva et al. suggested that their liposome delivery system may facilitate drug delivery through the tympanic membrane, but further in vivo and ex vivo experiments are needed to confirm this idea.²¹⁴

Periodontitis is a common chronic oral disease that may eventually lead to tooth loss. At present, the primary treatment is mechanical debridement combined with local antibiotic therapy. However, mechanical debridement may hinder periodontal tissue regeneration, and antibiotic therapy faces challenges, including drug resistance caused by biofilm and recurrent periodontitis caused by bacterial escape. Antibiotic-free strategy mediated by nanomaterials is helpful for the treatment of periodontitis. A novel injectable ointment (CN-PtNCs) effectively destroys biofilms of S. aureus and E. coli by photodynamic effect and has high bioavailability due to its injectable property.²¹⁵ Wayakanon et al. proposed a polymersome capable of carrying the drug into cells and collapsing in the lysosome to kill intracellular P. gingivalis.¹⁹⁵

Endophthalmitis is usually treated with invasive methods, such as intravitreal injections and surgery. Noninvasive and safer treatments based on NPs may improve the existing treatments. A dual-delivery system consisting of two NPs respectively loaded with azithromycin and triamcinolone acetonide improves bioavailability in choroid and retina and continuously releases the drug for 300 h, achieving a broad spectrum of antibacterial effect and anti-inflammatory effects.²¹⁶ Besides, the high frequency needed for using PA ophthalmic solution can also be solved by the slow-release property of the dual-delivery system.²¹⁷ Except for using antibacterial agents alone, combining with PTT can improve the efficiency of treatment either. AuAgCu₂O-bromfenac sodium NPs can eliminate MRSA through the combination of metal-mediated mild photothermal and photodynamic effects and the anti-inflammatory drug (bromfenac sodium) under safety.²¹⁸

CHALLENGES AND PERSPECTIVES

Owing to the malpractice use of antibiotics and the continuous emergence of new mechanisms of bacterial drug resistance, bacterial infections have become a major problem that threatens human health and public health safety. However, developing new drugs often takes a significant time, and searching for new targets is also a humongous difficulty. Nanomaterials have shown great prospects in the field of antimicrobial infections due to their unique physical and chemical properties, such as combating infections and drug resistance with antibiotic-free strategies, increasing the specificity and sensitivity of microbial diagnosis, improving the existing drugs as drug carriers, and participating in vaccine development as adjuvants and antigen carriers, and so on.

However, there are still significant obstacles to overcome before nanomaterials can be fully developed for clinical use.²¹⁹ Nanomaterials may be cytotoxic to some extent. Some metals (Ag, CuO, etc.) are cytotoxic to normal human cells, and some heavy metal ions penetrate cells, resulting in protein degeneration and other problems. Although many studies have addressed this issue, such as the reduction of cytotoxicity by adjusting the shape and size of these nanomaterials, or surface modification of nanomaterials with functional groups (quaternary ammonium salts) and polymers (chitosan modification), the specific mechanism remains to be further investigated. The pharmacokinetics of nano-based drugs have been rarely studied, despite that this must be clarified in the development of a new drug. Therefore, the in vivo process of these nanodrugs, such as whether they can effectively act on the human body through the appropriate administration route, whether they will cause additional damage to other organs and whether they will pass through some critical barriers in the body, should be one of the research directions in the future. In addition, there is no consensus on the mechanisms of some applications of nanomaterials, such as how nanomaterials enhance the body's immune response as adjuvants. This brings uncertainty to the therapeutic use of nanomaterials.

Except for the shortcomings of clinical application, the efficacy of nanomaterials in antimicrobial therapy has been challenged by the emerging bacterial drug resistance against nanomaterials. For example, bacteria will develop resistance through ion efflux pumps, expression of extracellular matrix, and mutation and adaptation of biofilms. Metal ions can promote the transfer of plasmid-mediated ARGs by increasing cell membrane permeability, changing mRNA gene expression level, and producing excessive ROS, which exacerbates the problem of bacterial resistance. How to solve this problem remains to be seen, although we have great expectations.

In summary, nanomaterials have shown great potential for anti-infection therapy, bringing hope to combat antibiotic resistance and reduce the side effects of traditional treatment. However, realizing a full-fledged nanomaterial drug remains a long way to go.

AUTHOR CONTRIBUTIONS

Yi Zou: Writing—original draft (equal); Writing—review and editing (equal). Shihan Tao: Writing—original draft (equal); Writing—review and editing (equal). Jing Li: Supervision (equal); Writing—review and editing (equal). Min Wu: Supervision (equal); Conceptualization (equal); Writing—review and editing (equal). Xikun Zhou: Supervision (equal); Conceptualization (equal); Writing—review and editing (equal). All authors have read and approved the final version.

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (No. 82241049, 82172285, 81922042, 82072999, and 82273320), the 1·3·5 project of excellent development of discipline of West China Hospital of Sichuan University (No. ZYYC21001), the Innovation Research Project of Sichuan University (No. 2022SCUH0029), and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004). We also acknowledge the contribution of BioRender with which part of our figures was created: .

CONFLICT OF INTEREST STATEMENT

Author Min Wu is an Editorial board member of MedComm – Biomaterials and Applications. Author Min Wu was not involved in the journal's review of or decisions related to this manuscript. The other authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

Not applicable.

ETHICS STATEMENT

The ethics statement is not applicable to this article.

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