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Review

Nanomedicine: New Frontiers in Fighting Microbial Infections

1
Department of NanoBiotechnology, Pasteur Institute of Iran, Tehran 13169-43551, Iran
2
Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran 19967-15433, Iran
3
Advanced Bioengineering Initiative Center, Multidisciplinary International Complex, K. N. Toosi University of Technology, Tehran 14176-14411, Iran
4
Centre for Biotechnology and Bioengineering (CBB), University of Waterloo, Waterloo, ON N2L 3G1, Canada
5
Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada
6
Data Science and Artificial Intelligence Program, College of Information Sciences and Technology (IST), Penn State University, State College, PA 16801, USA
7
Department of Chemical Engineering, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
8
School of Optometry and Vision Science, Faculty of Science, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada
*
Author to whom correspondence should be addressed.
Nanomaterials 2023, 13(3), 483; https://doi.org/10.3390/nano13030483 (registering DOI)
Received: 6 January 2023 / Revised: 21 January 2023 / Accepted: 22 January 2023 / Published: 25 January 2023

Abstract

:
Microbes have dominated life on Earth for the past two billion years, despite facing a variety of obstacles. In the 20th century, antibiotics and immunizations brought about these changes. Since then, microorganisms have acquired resistance, and various infectious diseases have been able to avoid being treated with traditionally developed vaccines. Antibiotic resistance and pathogenicity have surpassed antibiotic discovery in terms of importance over the course of the past few decades. These shifts have resulted in tremendous economic and health repercussions across the board for all socioeconomic levels; thus, we require ground-breaking innovations to effectively manage microbial infections and to provide long-term solutions. The pharmaceutical and biotechnology sectors have been radically altered as a result of nanomedicine, and this trend is now spreading to the antibacterial research community. Here, we examine the role that nanomedicine plays in the prevention of microbial infections, including topics such as diagnosis, antimicrobial therapy, pharmaceutical administration, and immunizations, as well as the opportunities and challenges that lie ahead.

1. Introduction

Antibiotics and vaccines are among the greatest medical advances. Over the previous century, broad-spectrum medicines and vaccinations greatly lowered infectious disease morbidity and mortality [1,2,3]. Infectious disease mortality in the US declined dramatically from 797 to 59 deaths per 100,000 between 1900 and 1996, with the lowest rate of 36 fatalities per 100,000 in 1980. In recent decades, some worrying patterns have evolved that jeopardize such progress. According to the World Health Organization’s Global Health Study from 2016, infectious and parasitic diseases are responsible for 9.7 percent of global deaths. The top five causes of death worldwide are as follows: TB (2.3%), diarrheal bacterial infections (2%), meningitis (0.5%), bacterial sexually transmitted disorders (syphilis, chlamydia, and gonorrhea, 0.2%), and encephalitis (0.2%) [4]. The Global Burden of Diseases consortium reports that Shigella and enterotoxigenic Escherichia coli are the most common and lethal bacteria that cause infectious diarrhea [5,6]. In 2016, infectious diarrhea was the eighth leading cause of death across all ages and the fifth leading cause of death among children. Pneumococcus is the largest cause of years of disability across the globe, due to an increase of 2.82 million cases of meningitis in 2016 [7]. About 11 million people died from sepsis-related causes in 2017 [8]. These numbers are significantly higher than the global average in impoverished nations because of the lack of universal health systems, public health issues, potable drinking water, and financial resources [4,6]. Antibiotic overuse has been linked to its emergence. Antibiotic ineffectiveness that is caused by rising drug resistance is a major threat to public health. Some researchers have even predicted that the 21st century will be the “postantibiotic era” [9,10]. Multidrug resistance (MDR) is a phenomenon that can occur in some bacteria [11]. Some multidrug-resistant infections are resistant to conventional therapies. An alarming example of multidrug resistance is the increasing number of strains of methicillin-resistant Staphylococcus aureus (MRSA) that are also resistant to vancomycin (VRSA), complicating therapy because vancomycin is usually the last line of defense against S. aureus infections [12]. Medication resistance, and new antimicrobial drugs, are falling behind the rapid pace at which microbes evolve [13]. On the other hand, traditional vaccinations that use live attenuated microorganisms, killed microbes, or microbial components, have proven to be crucial to infectious disease control, although some do not protect well. In addition, immunocompromised people should not utilize some live vaccines. No vaccinations are available for many infectious illnesses. In order to overcome these issues, a variety of vaccines that are based on isolated proteins, polysaccharides, or naked DNA encoding a protective antigen, are being produced. Although these can be safer, more defined, and less reactogenic than many vaccinations, they are often poor immunogens that need adjuvants to improve their activity. The pharmaceutical industry has slowed down the development of novel antibiotics, especially for MDR Gram-negative superbugs, due to low returns on investment and R&D objectives [14,15].
The pharmaceutical and biotechnology industries have been revolutionized by nanomedicine, or the application of nanotechnologies in medicine [16,17,18,19,20,21,22]. Clinical use approval has been granted for close to one hundred different nanomedicine products as of 2020. These products range from medication delivery and imaging to implantable biomaterials and medical devices [18]. Nanotechnologies can also tackle nearly every element of microbial illness (Figure 1). Nanomaterials’ unique physicochemical properties have helped to detect microbial diseases quickly, sensitively, and selectively. In addition, several inorganic and organic nanoparticles have significant intrinsic antibacterial capabilities that are rarely manifested in bulk form. More importantly, certain nanomaterials can reduce antibiotic resistance by weakening the resistance pathways. In addition, nanoparticles for antimicrobial drug delivery overcome resistance and have fewer adverse effects than the conventional antibiotics. Medical equipment can also inhibit bacteria adherence and infection by using antimicrobial nanoparticles. Last but not least, nanomaterials can boost immune responses to microbial illness as vaccine adjuvants or delivery vehicles. For antigens that would otherwise disintegrate quickly after injection, or cause a transient, the localized immune response can be delivered in a more stable form via encapsulation in nanoparticles. The possibility of integrating multiple antigens onto a single particle in order to protect against more than one illness is also being investigated, as is the use of nanoparticles to deliver vaccines by non-traditional routes, such as topical, inhalational, or optical delivery [23]. Here, we focus on the recent developments in nanotechnology that have been applied to the fight against infectious microbes.

2. Vaccination

It has been demonstrated that utilizing the host’s immune system to recognize and kill germs protects the host against microbial infection. Pathogen-associated molecular patterns help the innate immune system to identify pathogens that breach the host’s physical barriers [25]. Antigen-specific adaptive immune responses against bacterial infections can persist for decades after activating antigen-presenting cells (APCs) [26]. The protective response may delay bacteremia and septic shock, giving antibiotics more time to work. Microbe vaccines vary in immunogenicity and safety. Live attenuated bacterial vaccines raise concerns about pathogenicity reversion, vector immunity, and immune-compromised safety [27,28].
Isolated proteins, polysaccharides, and bare DNA are used to create next-generation bacterial vaccines, thanks to biotechnology [29]. Compared to vaccinations that are made from live, attenuated microbes, novel vaccines have a lower immune response. One possible answer lies in the use of nanotechnology to increase the effectiveness of vaccines on the immune system. Nanoparticle antigens elicit systemic and local humoral immune responses, including IgG and IgA antibodies and cellular responses from Th1, Th2, and Th17 cells [30]. Increased tissue penetration, access to the lymphatics, and preferential uptake by APCs are just a few examples of how nanoparticles can stimulate the immune system (Figure 2). Another way in which nanoparticles can do this includes the depot effect, which stabilizes the antigens and controls their sustained release. The depot effect involves the antigen and the adjuvant being displayed on the particle surface repeatedly in order to stimulate B cell receptor co-aggregation, triggering, and activation. Nanoparticle delivery technologies act as their adjuvants [30,31].
Nanoparticles deliver mucosal vaccinations well. Mucosal surfaces contain nearly 80% of immunocytes and are the first line of defense [32]. A total of 70% of pathogens enter the body through the mucosal surfaces [33]. Thus, a long-term mucosal immune response protects the host from bacterial infection. Mucosal vaccination induces mucosal and systemic immunity, while subcutaneous or intramuscular vaccines only induce a weak mucosal immune response [34]. Thus, intranasal, inhalational, and gastrointestinal mucosal vaccinations are becoming popular. Since the antigen must pass through several barriers before reaching the APCs, mucosal immunization is limited. Mucosal vaccination could benefit from immunostimulatory nanoparticle delivery vehicles [34]. The main sites of mucosal immunological activation are located in organized mucosa-associated lymphoid tissue (MALT), which can be reached by these nanoparticles. Antigen-loaded nanoparticles that are engineered with UEA-1 lectin, which selectively binds to M cells in MALT, have led to a two- to four-fold rise in antibody titers [35].

2.1. Adjuvant

Effective non-inflammatory mucosal adjuvants include nanoemulsions, which are oil-in-water emulsions containing droplets on the nanoscale [36]. Potentially enhanced antigen absorption, monocytes, and granulocyte recruitment, and cytokine and chemokine release, may result from nanoemulsion adjuvanticity [30]. After one or two mucosal injections, serum IgG and bronchial IgA and IgG antibodies were generated in mice and guinea pigs by recombinant anthrax protective antigens that were combined in nanoemulsion [37]. The commercial human anthrax vaccine schedule consists of six subcutaneous injections that are given at 18-month intervals, followed by annual booster shots. In order to boost immunity against Burkholderia, scientists used nanoemulsion as a novel mucosal adjuvant for the intranasal injection of Burkholderia multivorans outer membrane proteins antigen in vaccinated mice. Neutralizing activity against Burkholderia was demonstrated by these immune responses [38].
Cationic liposomes are used as an adjuvant in vaccinations. A cationic liposome-based adjuvant called CAF01 has been proven to improve vaccine-candidate immune responses and is currently in clinical testing [39]. In a study that was aimed at creating more effective and safer tuberculosis vaccines, researchers found that combining CAF01 with a synthetic mycobacterial glycolipid induced significant and protective Th1 and Th17 responses [40]. DC absorption and activation were prolonged by CAF01. The adjuvants for parenteral and mucosal vaccines were cationic liposomes containing non-coding plasmid DNA. Mice of the BALB/c strain were completely protected from a normally deadly lung challenge when they were given a liposome–DNA complex as a mucosal adjuvant along with heat-killed Burkholderia pseudomallei (B. pseudomallei) [41].

2.2. Vaccine Delivery

Small molecules, peptides, proteins, and nucleic acids can all be carried by polymeric nanoparticles. Antigens and adjuvants can be transported through synthetic polymers, which can then be injected into a patient [42]. An increase in CD4+ and CD8+ T cell subsets, and Th1 antibody titers that were 64-fold higher than Th2, were observed after exposure to PLGA nanoparticles expressing a recombinant major outer membrane protein of Chlamydia trachomatis (C. trachomatis) [43]. Inactivated bacterial toxoid vaccinations have been widely utilized to prevent and cure microbial illnesses by promoting antitoxin immunity. Eliminating toxin virulence while maintaining antigenicity is still difficult. Zhang and colleagues used erythrocyte membrane-coated polymeric nanoparticles to securely administer non-disrupted pore-forming toxins for immune processing (Figure 2) [44]. The nanoparticle-detained toxin gave mice a greater protection against toxin-mediated deleterious effects, neutralized poisons, and 100% survival. Chitosan and pullulan have been used to provide antigens against C. trachomatis and Streptococcus pneumonia [45,46]. Chitosan promoted cytokine synthesis, making it an adjuvant. Chitosan-modified antigen-loaded poly(e-caprolactone) nanoparticles increased IgG and IgA antibody responses [47].
In the case of protein oligomerization, self-assembling peptide nanoparticles (SAPNs) take the form of icosahedral symmetric assemblies. These aggregates are called “virus-like particles” (VLPs) due to their superficial similarity to viral capsids. SAPNs serve as a framework that allows for the highly exposed presentation of inserted protein epitopes or domains [48]. The introduction of different antigens into SAPNs can stimulate the production of antibodies against low-immunogenic antigens. In the absence of an adjuvant, animals that are immunized with SAPNs paired with an immunodominant B cell epitope that is derived from the circumsporozoite protein of Plasmodium berghei developed high-affinity, long-lasting T cell-dependent antibodies [49].
ISCOMs, or immune-stimulating complexes, are cage-like antigen delivery vehicles that are composed of cholesterol, phospholipid, and saponin [50]. ISCOMs have the potential to activate the IL-12-dependent components of the innate immune system and induce MHC class I and class II antigen presentation. ISCOMs have also demonstrated effectiveness as mucosal vaccines, especially when they are administered intranasally [51]. ISCOMs stimulate protective immune responses against Helicobacter pylori, Anaplasma marginale, Mycoplasma mycoides, Mycobacterium tuberculosis, Corynebacterium diphtheriae, Streptococcus pyogenes, Moraxella Bovis, and Chlamydia trachomatis [50].

3. Diagnosis

Contagious bacteria can spread infectious illnesses from sick people to healthy people. Thus, rapid, sensitive, and specific pathogen detection is essential for detecting infection sources, treating patients, and preventing illness [52,53]. Some of these illnesses are difficult to diagnose due to the complexity and diversity of the microorganisms and the long incubation period before the clinical symptoms arise (from minutes to years). ELISA and PCR are sensitive and reproducible molecular methods for microbial infection detection. However, these methods involve tedious sample preparation and extensive readout periods, which may delay time-critical infection detection and treatment, such as bacterial sepsis. These detection methods are also difficult to use in underdeveloped nations and rural parts of industrialized countries, where microbial infectious illnesses are more common.
Nanotechnology can produce rapid, sensitive, specific, and cost-effective microbial illness diagnosis methods [54]. Detecting target molecules/microbes in a complex sample matrix requires selective capture and separation. Nanotechnology can aid both of these processes, and nanoparticles’ unique physicochemical features may allow the recording of a single binding event. Nanoparticles containing affinity probes, such as antibodies and nucleic acids, can label or capture the targets by recognizing microbial biomarkers. Nanoscale ligand arrays that target specific pathogens and surface patterning could also significantly improve the detection of infectious diseases. Nanoparticles that are made of magnetic materials, gold (Au), and fluorescent dyes are used in microbiological diagnosis.

3.1. Magnetic Nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIONs) have been the subject of many studies as contrast agents for magnetic resonance imaging (MRI) [55,56,57]. Research on the use of magnetic nanoparticles that are coated with a probe in microbiological diagnostics has also progressed significantly in recent years. Lowery and coworkers created a SPION diagnostic technique based on T2-magnetic resonance (T2MR) that can detect five Candida species in whole blood samples in a fast manner and with high reproducibility within three hours [58]. The T2MR signal is significantly altered when oligonucleotide-decorated SPIONs hybridize with amplified Candida DNA (Figure 3). Based on this method, T2Candida is currently being utilized in clinical studies. Magneto-DNA nanoparticles were produced by Weissleder and colleagues for clinical pathogen profiling [24]. These nanoparticles target bacterial ribosomal RNA. Using a tiny nuclear magnetic resonance (NMR) device, the assay was able to detect and phenotype 13 different bacterial species that were present in the clinical specimens in under two hours.
Magnetic nanoparticles can be used to enrich, wash, and resuspend targets from a complex biological matrix with the help of magnetic fields that can be controlled. It is possible to identify bacteria in a sensitive and multiplex manner using this magnetic nanoparticle profile and new detection technologies. Matrix-assisted laser desorption/mass spectrometry, which is also known as MALDI-MS, is a technique that has been used to rapidly and accurately identify bacteria [60]. This technique is based on the mass spectrometry properties of common bacterial species. Rapid bacterial screening in clinical samples, such as whole blood, is made possible through magnetic nanoparticle-based sample preparation and concentration, as well as MALDI-MS detection [60,61]. In addition, ligand-modified magnetic nanoparticles and magnetic microfluidic devices can eliminate pathogens and endotoxins from the bloodstream [62,63]. When they are added to bovine whole blood, magnetic nanoparticles that have been coated with the synthetic ligand bis-Zn-DPA have the potential to eliminate E. coli with a clearance rate of around 100% at 60 mL/h.
In order to assess the metabolic activity and antibiotic resistance in bacteria, magnetic nanoparticles were used to track nutrient consumption (e.g., starch). In order to determine the susceptibility of bacteria in blood to antibiotics, Perez and colleagues [63] devised two methods based on SPION that make use of magnetic relaxation. Low metabolic activity or bacterial growth rates can trigger the assembly of Con A-conjugated SPIONs or dextran-coated SPIONs supplied with free Con A, resulting in a shift in T2MR. After 2.5 h, or 5 min, depending on whether or not free Con A is present, ampicillin susceptibility can be determined using a dextran-coated SPION competition assay. There is no need to incubate the sample cells for 24 h using this method, yet it provides just as precise an assessment of antibiotic sensitivity as the turbidity method.

3.2. Au Nanoparticles

Au nanoparticles’ unique optical and electrochemical characteristics, and their ability to be surface-functionalized with probes, have made them popular sensing materials [64]. Since Mirkin and colleagues’ pioneering work [65], oligonucleotide-functionalized Au nanoparticles have been frequently utilized as probes to quickly identify viruses whose genome sequences include distinctive nucleic acid fingerprints. Oligonucleotide–Au nanoparticles that are hybridized with target nucleic acids create a polymeric network and move the plasmon resonance peak [65]. Storhoff and colleagues devised a “spot-and-read” colorimetric approach for recognizing MRSA strains’ mecA genes using Au nanoparticles’ distance-dependent optical characteristics [66]. When they were spotted over an illuminated glass waveguide, these nanoparticles hybridized and changed color, detecting the nucleic acids with zeptomole sensitivity.
Au nanoparticle probes that are tagged with oligonucleotides and Raman-active dyes can be used for the multiplexed detection of oligonucleotide targets with good sensitivity and selectivity [67]. At 20 femtomolar concentrations, six distinct DNA targets were distinguished by Au nanoparticle probes that were tagged with Raman rays. Using this detection strategy, Mirkin and coworkers created a bio-barcode test for ultrasensitive nucleic acid and protein targets [68]. For magnetic separation and dithiothreitol (DTT)-mediated release of barcode strands, as shown in Figure 4, the targets of interest are sandwiched between Au nanoparticles and magnetic microparticles. The Verigene test, which was developed by Nanosphere, Inc., detects Gram-positive and Gram-negative bacteria directly from blood samples using in vitro methods. After a positive blood culture, the results can be delivered in 2–2.5 h with this test, compared to the normal 2–4 days with traditional microbiological procedures. This test is two- to three-orders-of-magnitude more sensitive than ELISA-based approaches [69].
Affinity probes besides oligonucleotides have been described and demonstrated to be useful for tagging Au nanoparticles for bacterial diagnosis. Gold nanoclusters that were enclosed in lysozymes and designed to interact with peptidoglycans on bacterial cell walls were produced to concentrate pathogenic germs for MALDIMS-based identification [70]. Stabilized gold nanoclusters against S. aureus and MRSA via human serum albumin or its binding peptide motif were produced [71]. Gold nanoparticle antimicrobial resistance can also be measured by monitoring the surface plasmon band shifts that are produced by Con A-induced clustering of extra-coated Au nanoparticles in a bacterial solution with starch [72].

3.3. Fluorescent Nanoparticles

Microbial detection has also been conducted with the use of nanomaterials or nanoparticles with fluorescent dyes. Antibody-conjugated silica nanoparticles containing hundreds of fluorescent dye molecules for signal amplification were produced by Tan and colleagues to allow for the in situ detection of single bacterial cells in less than twenty minutes [73]. Multicolored FRET silica nanoparticles were created by co-encapsulating three tandem dyes that emit various hues when they are excited with a single wavelength [74]. Different monoclonal antibody-conjugated FRET silica nanoparticles detected various bacterial targets simultaneously. Quantum dots (QDs), which are fluorescent semiconductor nanoparticles, have several advantages over traditional fluorophores, including photobleaching resistance and size-tunable wide absorption spectra with narrow emission [75]. QDs’ optical properties and variable surface chemistry make them a promising medium for complicated sample analysis and Listeria monocytogenes detection [76]. These affinity probes are promising for the high-throughput microbial identification of biological and environmental samples due to their chemical and physical plasticity and unique interactions with molecular targets or pathogens. Miniaturized devices with reduced sample quantities, quicker readouts, and improved sensitivity and accuracy will be created. Most nanoparticle-based diagnostic techniques use targeted probes to recognize known bacterial genome sequences/biomarkers and may not detect altered or novel bacteria strains. As drug-resistant strains grow, diagnostic nanotechnology that can detect germs and determine their sensitivity to antimicrobials is another key avenue.

4. Treatment

Antibiotic resistance is on the rise, posing a risk to the general population. Mutation and horizontal gene transfer are two mechanisms by which bacteria acquire resistance [77]. Reduced drug uptake and drug efflux from the microbial cell, the increased synthesis of a competitive inhibitor of antibiotics, and changes in the antibiotic-binding substrate are the root causes of antimicrobial drug resistance [78]. Chronic infections that are induced by biofilms and intracellular bacteria, including Mycobacterium leprae, Chlamydia, Listeria, and others, are another major obstacle in antimicrobial therapy [79,80]. Biofilm is an extracellular polymeric material (EPS) matrix that surrounds bacterial cells [81,82]. It traps and degrades antibiotic compounds, preventing diffusion. Biofilm bacteria can withstand various antibiotics 1000 times better than planktonic bacteria [83]. The host cell protects the intracellular bacteria from several drugs. Chronic infections require frequent high-dose antibiotics, therefore, their eradication is challenging.
Nanomedicine can cure microbial resistance without promoting it. Antimicrobial nanomaterials targeting numerous routes and the nanoparticle-based delivery of antibiotics might achieve this. Antimicrobial nanotherapeutics that suppress biofilms and target intracellular microorganisms may cure persistent infections. Nanomedicine is used to generate inorganic and organic nanomaterials with intrinsic antibacterial characteristics (Figure 5A) and nanoparticle-based antimicrobial medication delivery (Figure 5B).

4.1. Antimicrobial Nanomaterials

4.1.1. Inorganic Nanoparticles

Metals and metal oxides: For centuries, metals and metal oxides have been used as bactericidal agents in infection control [84,85,86]. Photocatalysis, photothermal effects, and ROS-stimulating activities are unique to metal and metal oxide nanoparticles [87,88]. These nanoparticles’ huge surface-area-to-volume ratio allows easy surface functionalization for more potent antibacterial agents.
Metal nanoparticles that are made of silver (Ag) have been studied the most extensively. Several drug-resistant organisms, including Pseudomonas aeruginosa, ampicillin-resistant Escherichia coli O157:H7, and erythromycin-resistant Streptococcus pyogenes, may be susceptible to their toxicity [89]. The effects of Ag on bacteria and other microorganisms are largely unknown. Ag compounds may be involved in bacterial cell death by both direct and indirect interactions with membranes, DNA, enzymes, and proteins [87]. The transport of Ag+ ions, which are formed when Ag is exposed to ambient O2 and dissolved in water, is essential for Ag’s antibacterial effect. Since smaller Ag nanoparticles have a higher surface-area-to-volume ratio, their rate of Ag+ release and antibacterial activity are affected [42,90]. When compared to bulk Ag, Ag nanoparticles have significantly higher antibacterial activity. Their surface roughness, hydrophobicity, oxidation state, and functionalization also impact Ag nanoparticles’ antibacterial activities [91]. For instance, glucosamine modification of Ag nanoparticles’ surfaces improves their antibacterial effectiveness by entering both Gram-negative and Gram-positive bacterial cells [92].
Tellurium (Te) and Bismuth (Bi) have also been researched for antibacterial therapy. The nanoparticles outperformed Ag nanoparticles in antibacterial activity and lower toxicity [93]. ZnO, CuO, TiO2, Al2O3, and CeO2 nanoparticles are also antibacterial [94]. For example, ZnO nanoparticles inhibit E. coli O157:H7 [95]. Metal oxide nanoparticles suppress bacteria by the photocatalytic creation of ROS (which destroys their cellular components), the reduction of bacterial membrane integrity, the disruption of energy transduction and transport activities, and the reduction in respiratory enzyme activity and DNA synthesis [96].
Metal and metal oxide nanoparticles as antimicrobials are hard for microorganisms to resist. Metals/metal oxides have several mechanisms of action, making microorganism resistance unlikely, unless multiple mutations occur concurrently. Ag, Bi, ZnO, and TiO2 nanoparticles also inhibit biofilm [97]. Bi nanoparticles reduced Streptococcus mutant’s growth by 69% and biofilm formation by 100% [98]. However, metal and metal oxide nanoparticles are mostly used in medical devices to prevent bacterial adhesion and infection. Safety concerns may limit their antimicrobial therapeutic use [99]. ZnO and TiO2 damage DNA, and CuO nanoparticles cause oxidative lesions [99]. Repeated injections accumulated Ag nanoparticles in the liver, the lung, and the spleen, which could damage these organs [100]. These findings suggest that chronic exposure should be monitored for toxicity. Furthermore, some metal and metal oxide nanomaterials may pose additional risks. Al2O3 nanoparticles promoted the horizontal conjugative transfer of MDR genes, increasing antibiotic resistance [101].
Carbon: Although they are still under research, carbon-based nanomaterials, including SWCNTs, MWCNTs, and fullerene, have been used in antibacterial applications [102]. These nanoparticles may kill bacteria through cell membrane disruption or photothermal/photodynamic characteristics [103]. Oxidative stress affects the bacterial membrane integrity and metabolic activity, making SWCNTs effective against Gram-positive and Gram-negative bacteria [104]. Fullerene has also been shown to be highly antibacterial. Some investigations imply that the oxidative by-products from fullerene production may cause toxicity [105]. Hydrophilic fullerene derivatives produce ROS efficiently and can be employed as photosensitizers in antimicrobial photodynamic treatment (PDT). Antimicrobial PDT illuminates microbial pathogens and develops no innate resistance [106].

4.1.2. Peptide- and Polymer-based Nanoparticles

Cationic peptides: Cationic antimicrobial peptides (CAPs)—nature’s antibiotics—are short amphipathic peptides that are found in all living forms, and they are effective against many microorganisms, including MDR bacteria [107]. High-multicellular organisms’ microbial defense systems include CAPs [108]. CAPs harm negatively charged microbial membranes, due to their cationic and hydrophobic characteristics. Cationic peptides’ cytotoxicity (e.g., hemolysis), enzymatic instability, and immunological surveillance restrict the antibacterial use of hundreds of CAP sequences [109]. Thus, placing CAPs on silica or paramagnetic nanoparticles protects the peptides from proteolytic breakdown and immunological recognition [110].
CAPs with cationic and amphipathic characteristics can self-assemble into nanostructures that are less toxic and more effective against bacteria in vivo than unassembled peptides [111]. Furthermore, nanostructure morphology has been linked to bioactivity, suggesting that the nanostructure itself may contribute to antibacterial activity [112]. Yang and colleagues created an amphiphilic peptide with cell-penetrating peptide TAT, six arginine residues, and cholesterol that can self-assemble into core–shell nanoparticles (Figure 6A,B) [111]. These nanoparticles can pass the blood–brain barrier and prevent bacterial growth in S. aureus-infected rabbit brains. One recent study showed that hydroponically modified CAPs and rifampicin synergistically treated multi-drug resistant and non-resistant TB and delayed rifampicin resistance [113]. Thus, CAP nanostructures that encapsulate and distribute antibiotics may improve the therapeutic effectiveness of combination therapies.
The advantages of the synthetic polymer analogs of CAPs include lower cost and improved enzymatic stability [114]. Comparable antibacterial processes can be found in quaternary ammonium and phosphonium polymers, which mimic CAPs. Figure 6C,D show the self-assembly of micellar nanoparticles that are made from a CAP-mimicking, amphiphilic triblock polymer. These nanoparticles suppress Gram-positive bacteria, MRSA, and fungi by destroying their membranes, and they do so without causing hemolysis at any dose. Even against Gram-negative E. coli and Gram-positive S. aureus, CAP-mimicking poly[2-(tert-butylamino)ethyl methacrylate] nanofibers containing Ag nanoparticles showed promising results [115].
Chitosan: Besides synthetic polymers, chitosan, which is a natural cationic polysaccharide polymer, exhibits antibacterial properties. Polycationic chitosan, and its derivatives, are antibacterial, due to their polycationic properties. The electrostatic contact increases the microbial wall permeability, and chelating essential trace metals inhibits enzymes [116]. Due to its larger surface-area-to-volume ratio and microbe attraction, nanoscale chitosan is a better antibacterial treatment than chitosan solution [117]. Chitosan nanoparticles had a MIC of 0.25 g/mL against E. coli and S. aureus, compared to 20 g/mL for normal chitosan molecules. Chitosan nanoparticles kill fungi and Gram-positive bacteria more effectively than Gram-negative bacteria [118]. In addition, Friedman and colleagues found that nanoparticles that are made of chitosan and alginate have direct bactericidal and anti-inflammatory capabilities by reducing P. acnes-induced cytokine production [119]. These nanoparticles proved to be a promising topical dermatologic therapy when they were encapsulated with benzoyl peroxide, which is an acne medication. Chitosan is hydrophilic and polycationic, making it a good carrier for antibiotics or a coating biomaterial for stabilizing metallic nanoparticles [120].
Figure 6. Images (A) and (B) are the chemical structure of the proposed peptide containing cholesterol, glycine, arginine, and TAT, and represent the formation of micelles. Reproduced with permission from [121], American Chemical Society, 2013. Images (C) and (D) are the chemical structure of cationic amphiphilic polycarbonate and represent the formation of micelles, as simulated by the Materials Studio program utilizing molecular modeling. Reproduced with permission from [122]. Copyright American Chemical Society, 2015.
Figure 6. Images (A) and (B) are the chemical structure of the proposed peptide containing cholesterol, glycine, arginine, and TAT, and represent the formation of micelles. Reproduced with permission from [121], American Chemical Society, 2013. Images (C) and (D) are the chemical structure of cationic amphiphilic polycarbonate and represent the formation of micelles, as simulated by the Materials Studio program utilizing molecular modeling. Reproduced with permission from [122]. Copyright American Chemical Society, 2015.
Nanomaterials 13 00483 g006

4.2. Drug Delivery

Nanoparticles provide antibacterial agents, which is another important use. Nanoparticle-based medication delivery might overcome antibiotic systemic toxicity, drug uptake and efflux, biofilm development, and intracellular bacterial infection. Surface modification with targeting ligands or microenvironment responsiveness can focus the nanoparticles on the infection site, improving therapeutic efficacy and reducing antimicrobial medication adverse effects. The nanoparticle distribution of antimicrobial medications also improves the hydrophobic drug solubility, the systemic circulation time, the drug half-life, and the drug release, which may minimize systemic adverse effects and the administration frequency [84,123,124,125,126]. Liposomes, solid lipid nanoparticles, polymers, silica, and Au nanoparticles have been produced to perform this [84,127]. Abelcet, AmBisome, Amphoteric, and Fungisome are some of the liposomal/lipid complex antibiotic delivery technologies that are licensed for human use.
Antibiotic resistance prevents microbial cells from attaining harmful drug concentrations through reduced uptake and enhanced efflux [77]. The outer membrane of Gram-negative bacteria, such as P. aeruginosa and E. coli, may also reduce the uptake of hydrophobic antibiotics, such as beta-lactams and macrolides [128]. An overexpression of transmembrane pumps increases efflux and confers MDR on microorganisms, typically resulting in resistance to chloramphenicol, fluoroquinolones, and macrolides [128]. Two recent reviews [129,130] have found that some nanoparticle delivery vehicles weaken these resistance mechanisms. Fusogenic liposomes that are made of specific lipids can fuse quickly with microbial plasma membranes and deliver a high drug concentration into the cytoplasm, saturating the transmembrane pumps [131].
Nanoparticle-based antibiotic delivery may help to fight biofilms and intracellular bacteria, which cause persistent infections that are hard to treat with traditional antimicrobials. Liposomes and lipid-/polymer-based nanoparticles shield antibiotics from enzymes and promote penetration, boosting their efficiency against biofilm-forming bacteria [132]. Liposome biofilm adherence might be increased by lipids such as phosphatidylinositol and stearyl amine [133]. Nanoparticles infiltrate the host cells through endocytic/phagocytic pathways and release their antibiotic payload into infection sites, due to their tiny size. The mononuclear phagocyte system clears nanoparticles from the body and houses numerous intracellular microorganisms [134]. Polyethylenimine-coated mesoporous silica nanoparticles that were loaded with rifampin were more effective against Mycobacterium tuberculosis-infected macrophages than free rifampin [135]. Nanoparticles for anti-biofilm and intracellular infection therapy have been widely examined in recent reviews [136].
Conjugating several antibiotic copies on nanomaterial surfaces can boost antibacterial effectiveness because some antibiotics interact with bacterial surface components. Au nanoparticles can attach antibiotic medicines to a solid surface and boost their antibacterial activity by interacting with the cell walls [137]. The effectiveness of vancomycin-capped Au nanoparticles in killing vancomycin-resistant Enterococcus and E. coli was increased by a factor of 64 compared to vancomycin alone [138]. Several studies have shown that the antibacterial activity of inert nanoparticles can be enhanced by the introduction of chemicals that are either inactive as antibiotics or are less active than antibiotics. Amino-substituted pyrimidine, which is inactive on its own, demonstrated a significant antibacterial effect against MDR clinical isolates after being conjugated on a Au nanoparticle surface [139].
Nanoparticles also deliver nitric oxide (NO), which is a short-lived gaseous antibacterial agent. NO inhibits DNA replication, cell respiration, and reactive nitrogen intermediate production, which makes it antibacterial [140]. These pathways prevent bacterial resistance to exogenous NO treatments [141]. Review publications [142,143] address several nanoparticle platforms for NO delivery. For instance, silica nanoparticles that are produced with NO donors (e.g., diazeniumdiolate) have outstanding antibacterial and biofilm-preventing activity (>99.9%) against P. aeruginosa and E. coli [144]. When NO donors were encapsulated in biomaterials, such as PAMAM dendrimer and chitosan, these nanoparticles had even greater bactericidal and anti-biofilm characteristics [145]. Besides encapsulating NO-donating compounds, Friedman and colleagues created a sol–gel-based nanoparticle system that can transport gaseous NO from the thermal reduction of nitrite and release it in a regulated and sustained way [146]. NO nanoparticles inhibited several bacteria, even drug-resistant ones. This solution holds NO in a stable state when it is dry and releases gaseous NO when it is wet, making it promising for the topical treatment of wounds and afflicted regions [147]. An MRSA-infected murine wound model showed rapid wound healing and reduced bacterial burden [148].
A combination antibiotic treatment may prevent and treat drug resistance [149]. Additive or synergistic effects can boost medication potency and antibacterial activity. Resistance to various drugs with diverse modes of action requires numerous gene changes in the same bacterial cell, which is unlikely. Nanoparticles might deliver several antibiotics and antimicrobial nanomaterials without synergistic/additive off-target effects. Rifampin and azithromycin-loaded PLGA nanoparticles were more effective against chlamydial infections than either treatment alone [150]. Mesoporous silica that was loaded with peracetic acid and Ag nanoparticles maintained their release and killed antibiotic-resistant and biofilm-forming S. aureus [151].
Antimicrobial drugs could be more effective if they were delivered to the location of infection via tailored nanoparticles rather than random ones. The treatment of slow-growing or dormant bacterial infections, which are notoriously difficult to treat and require regular high doses of antibiotics, may also benefit from this [152]. Ligand-modified nanoparticles are used in conventional targeting because of their specificity for binding to receptors on the surface of bacteria. Chlamydia infections, which upregulate folate receptor expression, were treated with azithromycin and rifampicin that were given by PLGA nanoparticles that were conjugated with folate. Liposomes containing ciprofloxacin that were mannose-conjugated showed high selectivity for alveolar macrophages and successfully cured intracellular respiratory tract infections [153].
A low pH, enzyme overexpression, localized bacterial toxins, and ligand-targeted nanoparticle delivery are some of the other targeting strategies that have been used [154]. Antibiotic efficiency is reduced due to the local acidity that is caused by the bacterial metabolism and the host immune response [155]. This process is the basis for the discovery of pH-responsive, surface-charge-switching nanoparticles that mask non-specific interactions at pH 7.4 but bind strongly to bacteria at pH 6.0 (Figure 7A,B). Vancomycin that is enclosed in nanoparticles is superior to free drugs at an acidic pH. (Figure 7C). Carboxyl-modified gold nanoparticles can be adsorbed to the exterior phospholipid layer of liposomes, allowing for the liposomes to be turned off at a neutral pH and turned back on at an acidic pH [156]. The combination of Au nanoparticles and liposomes in hydrogel allows for sustained localized drug delivery [157].
The enzymes and toxins that are produced by bacteria can be employed for site-specific applications. By incorporating themselves into the liposome membranes and releasing the encapsulated therapeutic drugs, novel liposomes that were generated by Zhang and colleagues can selectively deliver antibiotics to the areas of bacterial infection [158]. In order to ensure that only bacteria-producing lipase is treated with vancomycin, Wang and coworkers created a lipase-sensitive polymeric nanogel [159]. The drugs are released from the polymeric nanogel when bacterially produced lipase breaks down the nanogel’s polyphosphoester core and poly(e-caprolactone) barrier. The polymeric nanogel, which has been coupled with macrophage-targeting ligands such as mannose, first attaches to macrophages, then accumulates at the bacterial infection sites via macrophage-guided transport, and finally releases the antibiotics upon contact with the lipase-secreting bacteria [160].

5. Preclinical and Clinical Translation

5.1. Preclinical Translation: Animal-Tested Antimicrobial Nanoparticles

According to the type and the place of infection, nanoparticles that are compatible with the biological environment should be used. In the following subsections, the studies that have evaluated different nanoparticles against infections in animal models are discussed.

5.1.1. Skin and Subcutaneous Region Infection

Bacteria easily settle in skin lesions including atopic dermatitis and chronic wounds, contributing to infection-induced inflammation and disease progression [161]. Due to the obvious skin appearance, skin and subcutaneous infection are the best infection model for animal-based research of nanomedicine’s antimicrobial effectiveness. Topical or subcutaneous bacterium injections establish this infection model easily. Topical, subcutaneous, and intravenous nanoparticle distribution can treat cutaneous and subcutaneous infections. Au nanoparticles that were coated with chitosan and 2-mercapto-1-methylimidazole (MMT) interacted multivalently with bacterial membranes [162]. A gelatin wound dressing was made from nanoparticles and the nanoparticles were applied to a rabbit back wound that was infected with MRSA. The nanocomposite-treated wound closed by 92% after 16 days, while the gauze-treated wound closed by 67%. Liu et al. [163] developed polydopamine-coated Au nanorods for subcutaneous infection chemo-photothermal treatment. The polydopamine-coated nanorods loaded antibacterial Ag efficiently. Fluorescence imaging showed that this platform became positively charged in the acidic abscess, allowing bacteria to accumulate in the infection site. The loaded Ag released the pH sensitively. Under near-infrared (NIR) irradiation, mice received this nanosystem intravenously in order to cure a subcutaneous abscess. NIR hyperthermia increased Ag release and MRSA killing for abscess ablation and wound healing.
Garlic contains antimicrobial allicin [163]. Sharifi-Rad et al. [164] treated MRSA-infected mice with allicin and Ag nanoparticles. The allicin–Ag nanoparticle ointment inhibited the skin MRSA infection synergistically. A photothermal nanocomposite of HA-templated Ag nanoparticles combined with graphene oxide was created to treat skin S. aureus infection [165]. Bacterial hyaluronidase destroyed HA to liberate Ag. NIR light on graphene oxide nanoparticles localized hyperthermia in order to kill the microorganisms. In the in vivo skin wound infection investigation, the nanoparticles with NIR had two orders fewer bacteria than the control and NIR alone. Bacterial consortium and inflammation can result from CVC exposure. Ribeiro et al. [166] immobilized Slavonian A-functionalized SPIONs on CVC for antibacterial prophylaxis. CVC (40 mm) containing 20 μL of 1 × 109 CFU/mL K. of pneumonia caused mice to develop skin infections. A diode laser (808 nm) on the CVC for five minutes reduced the bacterial survival by 88%. The antimicrobial activity lasted for seven days. Cytokines lowered the inflammation. Acetylcysteine-coated Prussian blue nanoparticles enabled photothermal treatment [167]. Mucolytic antibacterial acetylcysteine and Prussian blue nanoparticles are NIR-triggered photothermal agents [168]. K4Fe(CN)6 and FeCl3 co-precipitated acetylcysteine-coated nanoparticles and NIR (980 nm) on the nanoparticles at 50 μg/mL killed S. aureus and E. coli by 74% and 75%, respectively. Subcutaneous abscesses were cured by NIR exposure following nanocomposite injection.
Carvacrol was incorporated into poly(-caprolactone) (PCL) nanocarriers and combined with hydrogel for topical distribution [169]. Monoterpene carvacrol kills several species of bacteria [170]. Bacterial lipase released carvacrol from enzyme-sensitive nanoparticles. Nanoparticle incorporation increased the carvacrol epidermal deposition from 0.04 to 0.96% of the administered dose in the dermatokinetic investigation. Carvacrol-loaded hydrogel nanoparticles reduced the MRSA burden by 99.97% in pig skin burn wounds. The hair follicles held 25% of the skin bacteria [171]. Eliminating hair follicle bacteria is challenging. Hsu et al. [172] created chloramphenicol-loaded lipid-based nanocarriers for follicular MRSA elimination. DMPC, or DA, was added to liposomes in order to create flexible vesicles for easy extrusion into the follicles. Flexible liposomes containing DMPC and DA increased intrafollicular drug uptake by 1.5- and 2-fold, respectively. Liposomes that were used topically for seven days did not cause skin irritation. Lipid-based nanoparticles can also be used to kill MRSA by combining SME and oxacillin in NLCs [173]. Cationic NLCs could disrupt MRSA membranes and leak proteins. Oxacillin entered the cytoplasm after membrane breakdown. Topical NLCs reduced the MRSA burden by four logs in mouse skin abscesses and NLCs restored the skin architecture and the barrier function.
Yang et al. [174] created lipid bilayer-coated gentamicin-loaded MSNs. Ubiquicidin adorned the MSN bilayer shells. Bacterial toxins could quickly release gentamicin from the lipid bilayer. Planktonic and intra-macrophage S. aureus showed rapid antibiotic release. Mice received intracellular S. aureus subcutaneously. After two days, the animals received nanocomposite intravenously. After PBS and free-medication injections, the infected regions had 2.3 × 107 and 8.4 × 106 CFU/mL, respectively. The nanoparticles reduced the bacteria to 1.5 × 104 CFU/mL. The surfactants formed micelles. The antibacterial SMEs were cationic surfactants that formed nanoscale micelles [175]. In the mouse model of subcutaneous MRSA abscess, topically administered SME micelles reduced the bacterial load by 1.6 × 104-fold compared to the vehicle control. Micelle’s intervention on healthy mouse skin caused minimal cutaneous irritation, suggesting that it is a safe anti-MRSA therapy.

5.1.2. Pulmonary Infection

Pneumonia, TB, and cystic fibrosis are caused by respiratory tract bacteria. Nanoformulations were administered intravenously or intratracheally to animals with lung infections. Tigecycline was the model antibiotic that was encapsulated in ICAM1-conjugated β-Ga2O3:Cr3+ nanoparticles by Kang et al. [176]. Inflammatory endothelial cells express ICAM1. Bioimaging semiconductor β-Ga2O3:Cr3+ is luminous [177]. In order to create TRKP-infected pneumonia mice, intratracheal tigecycline-resistant K. pneumoniae (TRKP) was injected into the lung. After 12 days, only the intravenous nanoparticle-treated animals survived the pulmonary infection. The free-drug-treated mice at 45 mg/kg had an 83% survival rate, which was lower than the nanocarrier-treated mice at 15 mg/kg. From 5 to 24 h post-injection, the nanoparticle-treated lung showed increased fluorescence intensity, suggesting targeted administration boosted nanoparticle accumulation in the diseased area.
Polymer-based nanocarriers alleviate P. aeruginosa-induced lung infection. Inhaled tobramycin cannot permeate DNA-rich lung mucus [178]. Deacon et al. [179] created tobramycin-loaded chitosan/alginate nanoparticles with DNase to reduce mucus viscoelasticity by DNA breakage. Pretreatment with biopolymer nanoparticles before lung infection with P. aeruginosa doubled the survival rate from 40% with free antibiotics to 80%. DNase-containing nanoparticles penetrated the cystic fibrosis sputum more effectively. Intratracheal PLGA nanoparticles carrying esculentin-1a cured lung infection in a study by Casciaro et al. [180]. PVA stabilized the nanoparticles. The pulmonary mucus easily permeated the neutral hydrophilic nanoparticles. Esculin-1a-loaded nanocarriers reduced CFU by three logs in P. aeruginosa-infected mice. Free esculentin-1a had 17-fold less anti-P. aeruginosa action. Micelle nanocarriers were made by conjugating vancomycin with amphiphilic PEG-co-PCL copolymer via pH-cleavable hydrazone linkages [181]. The nanocomposite contained on-demand ciprofloxacin. Under acidic conditions, the nanocomposite’s vancomycin shell opens, disrupting the hydrophilic/lipophilic balance and increasing the micelle size, which helps the lipase that is overexpressed in the infection site to degrade PCL and release ciprofloxacin to kill P. aeruginosa. The micelles reduced the lung bacterial load and the alveolar damage in P. aeruginosa-infected mice.
A ROS-responsive 4-(hydroxymethyl) phenylboronic acid pinacol ester-modified α-cyclodextrin was coated with phospholipids in order to generate lipid-coated nanoparticles in order to deliver moxifloxacin to infected lung tissue and sustain drug release [182]. In the inflammatory zone, nanocarriers that were coated with 1,2-stearoyl-sn-glycerol-3-phosphoethanolamine (DSPE)-PEG-folic acid allowed sputum to penetrate and target macrophages with overexpressed ROS. Mice with lung P. aeruginosa infections received the nanosystem intravenously. Moxifloxacin could increase the survival rate from 20% to 40% following nanoparticulate encapsulation. Nanocomposite therapy eliminated the lung pathogen colonies. PEGylated phosphatidylcholine-rich nanovesicles were tested for infectious pneumonia treatment [183]. Ciprofloxacin-loaded nanovesicles targeted lung surfactants. Intracellular MRSA may then disappear. After an intravenous injection of lipid nanovesicles, lung ciprofloxacin accumulation increased 3.2-fold in vivo. The control medication and nanovesicles reduced the pulmonary MRSA from 4.9 × 108 to 1.2 × 108 and 6.3 × 107 CFU, respectively.
Antimicrobial peptide NZX inhibits drug-resistant M. tuberculosis. Due to the macrophages’ high absorption of MSNs, Tenland et al. [184] tried to entrap NZX in them in order to cure tuberculosis. Nanoparticles killed intra-macrophage bacteria more effectively than free NZX. In the mouse tuberculosis model, intratracheal free peptide and NZX-containing MSNs lowered lung M. tuberculosis CFU by 84% and 88%, respectively. MSNs also actively targeted lung infections [185]. Vancomycin-loaded nanoparticles were coupled with S. aureus-recognizing cyclic 9-amino-acid peptide CARGGLKSC (CARG). CARG bound only to S. aureus in vitro. Intravenous CARG-conjugated nanoparticles had eight-fold more lung deposition than non-targeted nanoparticles. S. aureus that was instilled intratracheally into mouse lungs caused 67% mortality after 24 h. CARG-conjugated MSNs enhanced the survival rate to 100%. All MSN-treated mice survived for 20 days.

5.1.3. Gastrointestinal (GI) Infection

Oral antimicrobial nanoparticles treat gastrointestinal infections. Nanocarriers protect antibiotics against GI fluid breakdown. Bioadhesive nanoparticles prolong GI tract retention for oral bioavailability. Oral MSNs are suitable for GI medication enzymolysis protection. Zhao et al. [186] created intestine-targeted antimicrobial peptide defensin-loaded MSNs. The stomach degrades defensin. Succinylated casein, which intestinal protease may break down, was coated onto MSNs for intestinal targeting. In acidic conditions, casein ornamentation lowered the defensin release, while trypsin controlled it. Orally gavaged multidrug-resistant E. coli caused intestinal illness. Nanoparticles were taken orally daily for five days. The casein-coated nanomedicine reduced the bacteria colonization more than the free ciprofloxacin. Compared to the non-coated MSNs and the free peptides, the casein-coated nanoparticles lowered the intestinal TNF-α 1.5- and 2.2-fold.
Montmorillonite is a smectic clay with mucoadhesive and EPS-attaching properties [187]. H. pylori infection in GI patients was treated with a montmorillonite-cationic PEI metronidazole nanocomposite [188]. By acting as a biomimetic building block, montmorillonite can zero in on bacteria, while PEI can facilitate bacterial membrane rupturing, which improves the entry of antibiotics into the cytoplasm. Nanoparticles that are administered orally showed widespread distribution in the stomach tissue, demonstrating their mucoadhesion. Using nanocarriers to eliminate H. pylori in the gastrointestinal tract led to a reduction in gastric ulcers and inflammation. Compared to omeprazole, amoxicillin, and metronidazole, this triple therapy was more effective against germs. In order to create biomimetic nanocarriers for targeting H. pylori, the gastric epithelial cell membrane was coated onto PLGA nanoparticles [189]. H. pylori was attracted to the biomimetic nanocarriers 10 times more than to the uncoated nanoparticles. After the oral administration of the biomimetic nanoparticles and the free medicine, the bacterial burden in the stomachs of the infected mice was reduced from 1.6 105 CFU/g to 6.5 103 and 5.0 104, respectively.

5.1.4. The Other Infection Sites

Antibacterial nanoparticles have been used to treat systemic, bone, and vaginal infections. Systemic bacterial infections cause bacteremia and sepsis [190]. Rai et al. [191] coupled high-density antibacterial peptides on Ag nanoparticles in order to eliminate MRSA. This study used cecropin–melittin. Nanoparticles that are 14 nm might be regulated. Bacteremia was treated in septic-like animals with intraperitoneal Au nanoparticles. The circulation the MRSA concentration was two logs lower in the peptide-conjugated nanoparticle group. The spleens received most of the nanoparticles. Metallic nanoparticles were used to treat bone infections.
Ag–Cu nanoparticles by Qadri et al. [192] eliminated S. aureus bone infiltration in mice. Boron was added to nanoparticles in order to prolong antibacterial action because its anticorrosive properties delayed Cu oxidation [193]. The nanoparticles measured 27 nm. S. aureus was inserted into the mice’s bones with a silk suture in order to cause osteomyelitis. The 1 mg/kg intravenous nanoparticles reduced the bacterial CFU 10-fold compared to the control. The S. aureus bone accumulation was also suppressed intramuscularly. Magnetic Fe3O4 nanoparticles and heat-disrupted biofilm were used to cure osteomyelitis [194]. The S. aureus-infected bone received SPIONs. Infected bone magnetic fields were able to heat the implant to 75 °C. Vancomycin in the femoral canal during heating killed the biofilm microorganisms. Vancomycin and heat had 24% more bone volume than the infection control (18%). ZnO nanoparticles showed a low-concentration of antibacterial activity [195]. A PVA hydrogel containing 10 nm ZnO nanoparticles treated vaginitis vaginally [196]. Vaginal E. coli inoculation for five days caused vaginitis in mice. The nanoparticles reduced the CFU in vaginal washes. The histological epithelial exfoliation scores and the E. coli counts were consistent.

5.2. Clinical Trials

The good news is that nanosystem-based antibiotics, antitoxin compounds, and antimicrobial peptides have been transferred to the clinic after substantial research into revolutionary antimicrobial delivery systems to combat antibiotic resistance. Many are still undergoing clinical testing (Table 1).
In a Phase 1 trial in healthy volunteers, Lipoquin was used to inhale ciprofloxacin-loaded liposomes [196]. In 21 adult CF patients, a Phase 2a multi-center 14-day trial assessed Lipoquin’s efficacy, early safety, and pharmacokinetics. In similar regions, ORBIT-3 and ORBIT-4 were international, double-blind, randomized, Phase 3 trials of inhaled liposomal ciprofloxacin’s safety and efficacy [197,198]. Amikacin-loaded liposomes were also studied clinically. Individuals with a treatment-refractory nontuberculous mycobacteria lung infection on a stable multidrug regimen were compared to a placebo over the course of 84 days in a double-blind, randomized study testing the efficacy, safety, and tolerability of a once-daily amikacin 590 mg treatment [199]. For 18 months, patients with cystic fibrosis who had chronic Pseudomonas aeruginosa infections in Phase 2 trial breathed in 560 mg of amikacin-loaded liposomes once per day [200]. Liposomal amikacin (590 mg once per day for 12 months), in combination with the current gold-standard mycobacterial multi-drug regimen, for the treatment of mycobacterium abscesses in pulmonary illness will be tested in a Phase 2 trial in order to determine its efficacy, safety, and tolerability [201]. Studying the long-term safety and acceptability of inhaled amikacin-loaded liposome (590 mg/day) in individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection will be carried out in a Phase 3 clinical investigation [202].
Antibacterial drugs may benefit from a nano-preparation that targets bacterial toxins. In 2016, the first human monoclonal antibody targeting Clostridium difficile toxin B was approved, which was bezlotoxumab [203]. Monoclonal antibodies targeting S. aureus’ α-toxin and P. aeruginosa’s type III toxins secretory moiety are in clinical trials [204]. A broad-spectrum antitoxin liposomal compound (CAL02) has synergistic effects with medicines or antibiotics and can save mice from serious infections, such as staphylococci, by adsorbing toxins [205].
Antimicrobial peptides have broad-spectrum antibacterial action and little resistance risk due to their fast death [206]. Antimicrobial peptides target bacterial cell membranes. Nisin, nucleic acid, RNA, protein, and statins are intracellular targets [206].
Table 1. Nanomaterial-based antimicrobials in different stages of the clinical trial.
Table 1. Nanomaterial-based antimicrobials in different stages of the clinical trial.
AntimicrobialTrial PhaseApplicationRef.
AbelcetMarketedFungal infection[207]
AmBisomeMarketedFungal infection[208]
AmphotecMarketedFungal infection[209]
FungisomeMarketedFungal infection[210]
CiprofloxacinPhase 1Pseudomonas aeruginosa[211]
CiprofloxacinPhase 2aPseudomonas aeruginosa[211]
CiprofloxacinPhase 3Bronchiectasis and Chronic P. Aeruginosa Infection[197]
CiprofloxacinPhase 3Non-cystic fibrosis bronchiectasis (NCFB)[212]
AmikacinPhase 2Mycobacterium Infections, Nontuberculous[199]
AmikacinPhase 3Cystic Fibrosis Patients with Chronic Pseudomonas aeruginosa Infection[202]
AmikacinPhase 2Mycobacterium Infections, Nontuberculous Mycobacteria, Atypical[201]
AmikacinPhase 3Mycobacterium Infections, Nontuberculous[213]
AmikacinPhase 2Cystic Fibrosis[200]
Biological: CAL02Phase 3Severe community-acquired pneumonia[205]
Biological: GS-CDA1
Biological: MDX-1388
Phase 2Clostridium Difficile Associated Disease[214]
Novacta biosystems (NVB-302)Phase 1Clostridium difficile[215]
Human lactoferrin (hlf1-11)Phase 2Infection following transplantation[216]
(a potent cyclic lipodepsipeptides
antibiotic) Wap-8294A2
Phase 2Gm+ve bacteria (VRE and MRSA)[217]
The specifically targeted antimicrobialpeptide (C16G2)Phase 2Streptococcus mutans[218]
Antimicrobial Peptide (DPK-060)Phase 2Acute external otitis[219]
LTX-109 (Lytixar)Phase 2Nasal decolonization of MRSA Impetigo[220]
p2TA (AB 103)Phase 3Necrotizing soft tissue infections[198]
SurotomycinPhase 3Clostridium difficile[221]
Ramoplanin (NTI-851)Phase 2Clostridium difficile[222]

6. Concluding Remarks

Nanotechnology is promising for microbial illness treatment. Due to its high adjustability and broad range of adaptation, antibiotics with nanomaterials are a more cost-effective option for macrophage persister cells and biofilm infections. Nano-antibiotic systems can target, penetrate, absorb, and change infectious microenvironments, and combine with other treatment techniques due to their nanomaterial design. Thus, nanomaterials have considerable potential to improve antibiotic efficacy. Clinical translation must first resolve various issues and testify carefully about in vivo toxicity and clinical effects. Nano-antibiotics for resistant bacterial infections will require long-term research and practice before their widespread use. Nanomaterials are still a promising antibiotic-resistance-fighting option. We think that nano-antibiotics can combat bacterial resistance and save more lives soon.

Funding

This research received no external funding.

Data Availability Statement

The study did not report any data.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Armstrong, G.L.; Conn, L.A.; Pinner, R.W. Trends in Infectious Disease Mortality in the United States During the 20th Century. JAMA 1999, 281, 61–66. [Google Scholar] [CrossRef] [PubMed]
  2. Cohen, M.L. Changing patterns of infectious disease. Nature 2000, 406, 762–767. [Google Scholar] [CrossRef] [PubMed]
  3. Jadidi, A.; Salahinejad, E.; Sharifi, E.; Tayebi, L. Drug-delivery Ca-Mg silicate scaffolds encapsulated in PLGA. Int. J. Pharm. 2020, 589, 119855. [Google Scholar] [CrossRef] [PubMed]
  4. World Health Organization (WHO). Global Health Estimates 2016: Disease Burden by Cause, Age, Sex, by Country and by region, 2000–2016. 2018. Available online: https://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html (accessed on 28 October 2020).
  5. Khalil, I.A.; Troeger, C.; Blacker, B.F.; Rao, P.C.; Brown, A.; Atherly, D.E.; Brewer, T.G.; Engmann, C.M.; Houpt, E.R.; Kang, G. Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhea: The Global Burden of Disease Study 1990–2016. Lancet Infect. Dis. 2018, 18, 1229–1240. [Google Scholar] [CrossRef] [PubMed]
  6. GBD 2016 Diarrhoeal Disease Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of diarrhoea in 195 countries: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 2018, 18, 1211–1228. [Google Scholar] [CrossRef]
  7. Zunt, J.R.; Kassebaum, N.J.; Blake, N.; Glennie, L.; Wright, C.; Nichols, E.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; Adamu, A.A. Global, regional, and national burden of meningitis, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17, 1061–1082. [Google Scholar] [CrossRef]
  8. Rudd, K.E.; Johnson, S.C.; Agesa, K.M.; Shackelford, K.A.; Tsoi, D.; Kievlan, D.R.; Colombara, D.V.; Ikuta, K.S.; Kissoon, N.; Finfer, S. Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet 2020, 395, 200–211. [Google Scholar] [CrossRef]
  9. Kåhrström, C.T. Entering a post-antibiotic era? Nat. Rev. Genet. 2013, 11, 146. [Google Scholar] [CrossRef]
  10. Lv, X.; Zhang, J.; Yang, D.; Shao, J.; Wang, W.; Zhang, Q.; Dong, X. Recent advances in pH-responsive nanomaterials for anti-infective therapy. J. Mater. Chem. B 2020, 8, 10700–10711. [Google Scholar] [CrossRef]
  11. Alekshun, M.N.; Levy, S.B. Molecular Mechanisms of Antibacterial Multidrug Resistance. Cell 2007, 128, 1037–1050. [Google Scholar] [CrossRef]
  12. Limbago, B.M.; Kallen, A.J.; Zhu, W.; Eggers, P.; McDougal, L.K.; Albrecht, V.S. Report of the 13th vancomycin-resistant Staph-ylococcus aureus isolate from the United States. J. Clin. Microbiol. 2014, 52, 998–1002. [Google Scholar] [CrossRef]
  13. Schäberle, T.F.; Hack, I.M. Overcoming the current deadlock in antibiotic research. Trends Microbiol. 2014, 22, 165–167. [Google Scholar] [CrossRef]
  14. Taubes, G. The Bacteria Fight Back; American Association for the Advancement of Science: Washington, DC, USA, 2008. [Google Scholar]
  15. Boucher, H.W.; Talbot, G.H.; Benjamin, D.K., Jr.; Bradley, J.; Guidos, R.J.; Jones, R.N.; Murray, B.E.; Bonomo, R.A.; Gilbert, D. 10 × ‘20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update from the Infectious Diseases Society of America. Clin. Infect. Dis. 2013, 56, 1685–1694. [Google Scholar] [CrossRef]
  16. Kashkooli, F.M.; Soltani, M.; Souri, M. Controlled anti-cancer drug release through advanced nano-drug delivery systems: Static and dynamic targeting strategies. J. Control. Release 2020, 327, 316–349. [Google Scholar] [CrossRef]
  17. Kashkooli, F.M.; Soltani, M.; Souri, M.; Meaney, C.; Kohandel, M. Nexus between in silico and in vivo models to enhance clinical translation of nanomedicine. Nano Today 2021, 36, 101057. [Google Scholar] [CrossRef]
  18. Souri, M.; Soltani, M.; Kashkooli, F.M.; Shahvandi, M.K.; Chiani, M.; Shariati, F.S.; Mehrabi, M.R.; Munn, L.L. Towards principled design of cancer nanomedicine to accelerate clinical translation. Mater. Today Bio 2022, 13, 100208. [Google Scholar] [CrossRef]
  19. Souri, M.; Soltani, M.; Kashkooli, F.M.; Shahvandi, M.K. Engineered strategies to enhance tumor penetration of drug-loaded nanoparticles. J. Control. Release 2022, 341, 227–246. [Google Scholar] [CrossRef]
  20. Soltani, M.; Kashkooli, F.M.; Souri, M.; Harofte, S.Z.; Harati, T.; Khadem, A.; Pour, M.H.; Raahemifar, K. Enhancing Clinical Translation of Cancer Using Nanoinformatics. Cancers 2021, 13, 2481. [Google Scholar] [CrossRef]
  21. Souri, M.; Chiani, M.; Farhangi, A.; Mehrabi, M.R.; Nourouzian, D.; Raahemifar, K.; Soltani, M. Anti-COVID-19 Nanomaterials: Directions to Improve Prevention, Diagnosis, and Treatment. Nanomaterials 2022, 12, 783. [Google Scholar] [CrossRef]
  22. Hu, Y.; Li, H.; Lv, X.; Xu, Y.; Xie, Y.; Yuwen, L.; Song, Y.; Li, S.; Shao, J.; Yang, D. Stimuli-responsive therapeutic systems for the treatment of diabetic infected wounds. Nanoscale 2022, 14, 12967–12983. [Google Scholar] [CrossRef]
  23. Gregory, A.E.; Titball, R.; Williamson, D. Vaccine delivery using nanoparticles. Front. Cell. Infect. Microbiol. 2013, 3, 13. [Google Scholar] [CrossRef] [PubMed]
  24. Zhu, X.; Radovic-Moreno, A.F.; Wu, J.; Langer, R.; Shi, J. Nanomedicine in the management of microbial infection—Overview and perspectives. Nano Today 2014, 9, 478–498. [Google Scholar] [CrossRef] [PubMed]
  25. Plotkin, S.A. Vaccines: Past, present and future. Nat. Med. 2005, 11, S5–S11. [Google Scholar] [CrossRef]
  26. Choh, L.-C.; Ong, G.-H.; Vellasamy, K.M.; Kalaiselvam, K.; Kang, W.-T.; Al-Maleki, A.R.; Mariappan, V.; Vadivelu, J. Burkholderia vaccines: Are we moving forward? Front. Cell. Infect. Microbiol. 2013, 3, 5. [Google Scholar] [CrossRef] [PubMed]
  27. Curtiss, R. Bacterial infectious disease control by vaccine development. J. Clin. Investig. 2002, 110, 1061–1066. [Google Scholar] [CrossRef]
  28. Carleton, H.A. Combating Evolving Pathogens: Pathogenic Bacteria as Vaccine Vectors: Teaching Old Bugs New Tricks. Yale J. Biol. Med. 2010, 83, 217. [Google Scholar]
  29. Peek, L.J.; Middaugh, C.R.; Berkland, C. Nanotechnology in vaccine delivery. Adv. Drug Deliv. Rev. 2008, 60, 915–928. [Google Scholar] [CrossRef]
  30. Smith, D.M.; Simon, J.K.; Baker, J.R., Jr. Applications of nanotechnology for immunology. Nat. Rev. Immunol. 2013, 13, 592–605. [Google Scholar] [CrossRef]
  31. Reddy, S.T.; van der Vlies, A.J.; Simeoni, E.; Angeli, V.; Randolph, G.J.; O’Neil, C.P.; Lee, L.K.; Swartz, M.A.; Hubbell, J.A. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 2007, 25, 1159–1164. [Google Scholar] [CrossRef]
  32. Holmgren, J.; Czerkinsky, C. Mucosal immunity and vaccines. Nat. Med. 2005, 11, S45–S53. [Google Scholar] [CrossRef]
  33. Neutra, M.R.; Pringault, E.; Kraehenbuhl, J.-P. Antigen Sampling Across Epithelial Barriers and Induction of Mucosal Immune Responses. Annu. Rev. Immunol. 1996, 14, 275–300. [Google Scholar] [CrossRef]
  34. Kammona, O.; Kiparissides, C. Recent advances in nanocarrier-based mucosal delivery of biomolecules. J. Control. Release 2012, 161, 781–794. [Google Scholar] [CrossRef]
  35. Manocha, M.; Pal, P.C.; Chitralekha, K.; Thomas, B.E.; Tripathi, V.; Gupta, S.D.; Paranjape, R.; Kulkarni, S.; Rao, D.N. Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG mi-croparticles in combination with Ulex europaeus-I lectin as M cell target. Vaccine 2005, 23, 5599–5617. [Google Scholar] [CrossRef] [PubMed]
  36. Hamouda, T.; Myc, A.; Donovan, B.; Shih, A.Y.; Reuter, J.D.; Baker, J.R. A novel surfactant nanoemulsion with a unique non-irritant topical antimicrobial activity against bacteria, enveloped viruses and fungi. Microbiol. Res. 2001, 156, 1–7. [Google Scholar] [CrossRef]
  37. Bielinska, A.U.; Janczak, K.W.; Landers, J.J.; Makidon, P.; Sower, L.E.; Peterson, J.W.; Baker, J.R., Jr. Mucosal immunization with a novel nanoemulsion-based recombinant anthrax protective antigen vaccine protects against Bacillus anthracis spore chal-lenge. Infect. Immun. 2007, 75, 4020–4029. [Google Scholar] [CrossRef]
  38. Makidon, P.E.; Knowlton, J.; Groom, J.V.; Blanco, L.P.; Lipuma, J.J.; Bielinska, A.U.; Baker, J.R. Induction of immune response to the 17 kDa OMPA Burkholderia cenocepacia polypeptide and protection against pulmonary infection in mice after nasal vaccination with an OMP nanoemulsion-based vaccine. Med. Microbiol. Immunol. 2010, 199, 81–92. [Google Scholar] [CrossRef]
  39. Martel, C.J.-M.; Agger, E.M.; Poulsen, J.J.; Jensen, T.H.; Andresen, L.; Christensen, D.; Nielsen, L.P.; Blixenkrone-Møller, M.; Andersen, P.; Aasted, B. CAF01 Potentiates Immune Responses and Efficacy of an Inactivated Influenza Vaccine in Ferrets. PLoS ONE 2011, 6, e22891. [Google Scholar] [CrossRef]
  40. Kamath, A.T.; Rochat, A.-F.; Christensen, D.; Agger, E.M.; Andersen, P.; Lambert, P.-H.; Siegrist, C.-A. A liposome-based my-cobacterial vaccine induces potent adult and neonatal multifunctional T cells through the exquisite targeting of dendritic cells. PLoS ONE 2009, 4, e5771. [Google Scholar] [CrossRef]
  41. Henderson, A.; Propst, K.; Kedl, R.; Dow, S. Mucosal immunization with liposome-nucleic acid adjuvants generates effective humoral and cellular immunity. Vaccine 2011, 29, 5304–5312. [Google Scholar] [CrossRef] [PubMed]
  42. Blecher, K.; Nasir, A.; Friedman, A. The growing role of nanotechnology in combating infectious disease. Virulence 2011, 2, 395–401. [Google Scholar] [CrossRef]
  43. Fairley, S.J.; Singh, S.R.; Yilma, A.N.; Waffo, A.B.; Subbarayan, P.; Dixit, S.; Taha, M.A.; Cambridge, C.D.; Dennis, V.A. Chlamydia trachomatis recombinant MOMP encapsulated in PLGA nanoparticles triggers primarily T helper 1 cellular and antibody immune responses in mice: A desirable candidate nanovaccine. Int. J. Nanomed. 2013, 8, 2085–2099. [Google Scholar] [CrossRef]
  44. Hu, C.-M.J.; Fang, R.H.; Luk, B.T.; Zhang, L. Nanoparticle-detained toxins for safe and effective vaccination. Nat. Nanotechnol. 2013, 8, 933–938. [Google Scholar] [CrossRef]
  45. Kong, I.G.; Sato, A.; Yuki, Y.; Nochi, T.; Takahashi, H.; Sawada, S.; Mejima, M.; Kurokawa, S.; Okada, K.; Sato, S.; et al. Nanogel-Based PspA Intranasal Vaccine Prevents Invasive Disease and Nasal Colonization by Streptococcus pneumoniae. Infect. Immun. 2013, 81, 1625–1634. [Google Scholar] [CrossRef] [PubMed]
  46. Cambridge, C.D.; Singh, S.R.; Waffo, A.B.; Fairley, S.J.; Dennis, V.A. Formulation, characterization, and expression of a re-combinant MOMP Chlamydia trachomatis DNA vaccine encapsulated in chitosan nanoparticles. Int. J. Nanomed. 2013, 8, 1759–1771. [Google Scholar]
  47. Florindo, H.; Pandit, S.; Lacerda, L.; Gonçalves, L.; Alpar, H.; Almeida, A. The enhancement of the immune response against S. equi antigens through the intranasal administration of poly-ɛ-caprolactone-based nanoparticles. Biomaterials 2009, 30, 879–891. [Google Scholar] [CrossRef]
  48. Schroeder, U.; Graff, A.; Buchmeier, S.; Rigler, P.; Silvan, U.; Tropel, D.; Jockusch, B.M.; Aebi, U.; Burkhard, P.; Schoenenberger, C.-A. Peptide Nanoparticles Serve as a Powerful Platform for the Immunogenic Display of Poorly Antigenic Actin Determinants. J. Mol. Biol. 2009, 386, 1368–1381. [Google Scholar] [CrossRef]
  49. Kaba, S.A.; Brando, C.; Guo, Q.; Mittelholzer, C.; Raman, S.; Tropel, D.; Aebi, U.; Burkhard, P.; Lanar, D.E. A nonadjuvanted pol-ypeptide nanoparticle vaccine confers long-lasting protection against rodent malaria. J. Immunol. 2009, 183, 7268–7277. [Google Scholar] [CrossRef]
  50. Sun, H.-X.; Xie, Y.; Ye, Y.-P. ISCOMs and ISCOMATRIX™. Vaccine 2009, 27, 4388–4401. [Google Scholar] [CrossRef]
  51. Hu, K.-F.; Lövgren-Bengtsson, K.; Morein, B. Immunostimulating complexes (ISCOMs) for nasal vaccination. Adv. Drug Deliv. Rev. 2001, 51, 149–159. [Google Scholar] [CrossRef]
  52. Salyers, A.A.; Whitt, D.D.; Whitt, D.D. Bacterial Pathogenesis: A Molecular Approach; ASM Press: Washington, DC, USA, 1994. [Google Scholar]
  53. Allegranzi, B.; Nejad, S.B.; Combescure, C.; Graafmans, W.; Attar, H.; Donaldson, L.; Pittet, D. Burden of endemic health-care-associated infection in developing countries: Systematic review and meta-analysis. Lancet 2011, 377, 228–241. [Google Scholar] [CrossRef]
  54. Kaittanis, C.; Santra, S.; Perez, J.M. Emerging nanotechnology-based strategies for the identification of microbial pathogenesis. Adv. Drug Deliv. Rev. 2010, 62, 408–423. [Google Scholar] [CrossRef]
  55. Xie, J.; Liu, G.; Eden, H.S.; Ai, H.; Chen, X. Surface-Engineered Magnetic Nanoparticle Platforms for Cancer Imaging and Therapy. Acc. Chem. Res. 2011, 44, 883–892. [Google Scholar] [CrossRef]
  56. Souri, M.; Kashkooli, F.M.; Soltani, M. Analysis of Magneto-Hyperthermia Duration in Nano-sized Drug Delivery System to Solid Tumors Using Intravascular-Triggered Thermosensitive-Liposome. Pharm. Res. 2022, 39, 753–765. [Google Scholar] [CrossRef]
  57. Souri, M.; Soltani, M.; Kashkooli, F.M. Computational modeling of thermal combination therapies by magneto-ultrasonic heating to enhance drug delivery to solid tumors. Sci. Rep. 2021, 11, 19539. [Google Scholar] [CrossRef]
  58. Chow, E.K.-H.; Ho, D. Cancer Nanomedicine: From Drug Delivery to Imaging. Sci. Transl. Med. 2013, 5, 216rv4. [Google Scholar] [CrossRef]
  59. Neely, L.A.; Audeh, M.; Phung, N.A.; Min, M.; Suchocki, A.; Plourde, D.; Blanco, M.; Demas, V.; Skewis, L.R.; Anagnostou, T.; et al. T2 Magnetic Resonance Enables Nanoparticle-Mediated Rapid Detection of Candidemia in Whole Blood. Sci. Transl. Med. 2013, 5, 182ra54. [Google Scholar] [CrossRef]
  60. Bizzini, A.; Durussel, C.; Bille, J.; Greub, G.; Prod’Hom, G. Performance of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Bacterial Strains Routinely Isolated in a Clinical Microbiology Laboratory. J. Clin. Microbiol. 2010, 48, 1549–1554. [Google Scholar] [CrossRef]
  61. Lin, Y.-S.; Tsai, P.-J.; Weng, M.-F.; Chen, Y.-C. Affinity Capture Using Vancomycin-Bound Magnetic Nanoparticles for the MALDI-MS Analysis of Bacteria. Anal. Chem. 2005, 77, 1753–1760. [Google Scholar] [CrossRef]
  62. Lee, J.-J.; Jeong, K.J.; Hashimoto, M.; Kwon, A.H.; Rwei, A.; Shankarappa, S.A.; Tsui, J.H.; Kohane, D.S. Synthetic Ligand-Coated Magnetic Nanoparticles for Microfluidic Bacterial Separation from Blood. Nano Lett. 2014, 14, 1–5. [Google Scholar] [CrossRef]
  63. Kaittanis, C.; Nath, S.; Perez, J.M. Rapid Nanoparticle-Mediated Monitoring of Bacterial Metabolic Activity and Assessment of Antimicrobial Susceptibility in Blood with Magnetic Relaxation. PLoS ONE 2008, 3, e3253. [Google Scholar] [CrossRef]
  64. Uehara, N. Polymer-functionalized Gold Nanoparticles as Versatile Sensing Materials. Anal. Sci. 2010, 26, 1219–1228. [Google Scholar] [CrossRef] [PubMed]
  65. Elghanian, R.; Storhoff, J.J.; Mucic, R.C.; Letsinger, R.L.; Mirkin, C.A. Selective Colorimetric Detection of Polynucleotides Based on the Distance-Dependent Optical Properties of Gold Nanoparticles. Science 1997, 277, 1078–1081. [Google Scholar] [CrossRef]
  66. Storhoff, J.J.; Lucas, A.D.; Garimella, V.; Bao, Y.P.; Müller, U.R. Homogeneous detection of unamplified genomic DNA sequences based on colorimetric scatter of gold nanoparticle probes. Nat. Biotechnol. 2004, 22, 883–887. [Google Scholar] [CrossRef] [PubMed]
  67. Cao, Y.C.; Jin, R.; Mirkin, C.A. Nanoparticles with Raman Spectroscopic Fingerprints for DNA and RNA Detection. Science 2002, 297, 1536–1540. [Google Scholar] [CrossRef] [PubMed]
  68. Hill, H.D.; Mirkin, C.A. The bio-barcode assay for the detection of protein and nucleic acid targets using DTT-induced ligand exchange. Nat. Protoc. 2006, 1, 324–336. [Google Scholar] [CrossRef]
  69. Scott, L.J. Verigene® Gram-Positive Blood Culture Nucleic Acid Test. Mol. Diagn. Ther. 2013, 17, 117–122. [Google Scholar] [CrossRef]
  70. Chan, P.-H.; Wong, S.-Y.; Lin, S.-H.; Chen, Y.-C. Lysozyme-encapsulated gold nanocluster-based affinity mass spectrometry for pathogenic bacteria. Rapid Commun. Mass Spectrom. 2013, 27, 2143–2148. [Google Scholar] [CrossRef]
  71. Chan, P.-H.; Chen, Y.-C. Human serum albumin stabilized gold nanoclusters as selective luminescent probes for Staphylo-coccus aureus and methicillin-resistant Staphylococcus aureus. Anal. Chem. 2012, 84, 8952–8956. [Google Scholar] [CrossRef]
  72. Nath, S.; Kaittanis, C.; Tinkham, A.; Perez, J.M. Dextran-coated gold nanoparticles for the assessment of antimicrobial suscep-tibility. Anal. Chem. 2008, 80, 1033–1038. [Google Scholar] [CrossRef]
  73. Zhao, X.; Hilliard, L.R.; Mechery, S.J.; Wang, Y.; Bagwe, R.P.; Jin, S.; Tan, W. A rapid bioassay for single bacterial cell quantitation using bioconjugated nanoparticles. Proc. Natl. Acad. Sci. USA 2004, 101, 15027–15032. [Google Scholar] [CrossRef]
  74. Wang, L.; Zhao, W.; O’Donoghu, M.B.; Tan, W. Fluorescent Nanoparticles for Multiplexed Bacteria Monitoring. Bioconjugate Chem. 2007, 18, 297–301. [Google Scholar] [CrossRef]
  75. Zrazhevskiy, P.; Sena, M.; Gao, X. Designing multifunctional quantum dots for bioimaging, detection, and drug delivery. Chem. Soc. Rev. 2010, 39, 4326–4354. [Google Scholar] [CrossRef]
  76. Tully, E.; Hearty, S.; Leonard, P.; O’Kennedy, R. The development of rapid fluorescence-based immunoassays, using quantum dot-labelled antibodies for the detection of Listeria monocytogenes cell surface proteins. Int. J. Biol. Macromol. 2006, 39, 127–134. [Google Scholar] [CrossRef]
  77. Jayaraman, R. Antibiotic resistance: An overview of mechanisms and a paradigm shift. Curr. Sci. 2009, 96, 1475–1484. [Google Scholar]
  78. Pelgrift, R.Y.; Friedman, A.J. Nanotechnology as a therapeutic tool to combat microbial resistance. Adv. Drug Deliv. Rev. 2013, 65, 1803–1815. [Google Scholar] [CrossRef]
  79. Ray, K.; Marteyn, B.; Sansonetti, P.J.; Tang, C.M. Life on the inside: The intracellular lifestyle of cytosolic bacteria. Nat. Rev. Genet. 2009, 7, 333–340. [Google Scholar] [CrossRef]
  80. Lv, X.; Wang, L.; Mei, A.; Xu, Y.; Ruan, X.; Wang, W.; Shao, J.; Yang, D.; Dong, X. Recent Nanotechnologies to Overcome the Bacterial Biofilm Matrix Barriers. Small 2022, 2206220. [Google Scholar] [CrossRef]
  81. Mah, T.-F.C.; O’Toole, G.A. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001, 9, 34–39. [Google Scholar] [CrossRef]
  82. Hu, Y.; Ruan, X.; Lv, X.; Xu, Y.; Wang, W.; Cai, Y.; Ding, M.; Dong, H.; Shao, J.; Yang, D.; et al. Biofilm microenvironment-responsive nanoparticles for the treatment of bacterial infection. Nano Today 2022, 46, 101602. [Google Scholar] [CrossRef]
  83. Huang, L.; Dai, T.; Xuan, Y.; Tegos, G.P.; Hamblin, M.R. Synergistic Combination of Chitosan Acetate with Nanoparticle Silver as a Topical Antimicrobial: Efficacy against Bacterial Burn Infections. Antimicrob. Agents Chemother. 2011, 55, 3432–3438. [Google Scholar] [CrossRef]
  84. Huh, A.J.; Kwon, Y.J. “Nanoantibiotics”: A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era. J. Control. Release 2011, 156, 128–145. [Google Scholar] [CrossRef] [PubMed]
  85. Tran, N.; Tran, P. Nanomaterial-Based Treatments for Medical Device-Associated Infections. ChemPhysChem 2012, 13, 2481–2494. [Google Scholar] [CrossRef]
  86. Makvandi, P.; Wang, C.Y.; Zare, E.N.; Borzacchiello, A.; Niu, L.N.; Tay, F.R. Metal-Based Nanomaterials in Biomedical Applications: Antimicrobial Activity and Cytotoxicity Aspects. Adv. Funct. Mater. 2020, 30, 1910021. [Google Scholar] [CrossRef]
  87. Eckhardt, S.; Brunetto, P.S.; Gagnon, J.; Priebe, M.; Giese, B.; Fromm, K.M. Nanobio Silver: Its Interactions with Peptides and Bacteria, and Its Uses in Medicine. Chem. Rev. 2013, 113, 4708–4754. [Google Scholar] [CrossRef] [PubMed]
  88. Yougbaré, S.; Chou, H.-L.; Yang, C.-H.; Krisnawati, D.I.; Jazidie, A.; Nuh, M.; Kuo, T.-R. Facet-dependent gold nanocrystals for effective photothermal killing of bacteria. J. Hazard. Mater. 2021, 407, 124617. [Google Scholar] [CrossRef] [PubMed]
  89. Lara, H.H.; Ayala-Núnez, N.V.; del Carmen Ixtepan Turrent, L.; Rodríguez Padilla, C. Bactericidal effect of silver nanoparticles against multidrug-resistant bacteria. World J. Microbiol. Biotechnol. 2010, 26, 615–621. [Google Scholar] [CrossRef]
  90. Knetsch, M.L.W.; Koole, L.H. New Strategies in the Development of Antimicrobial Coatings: The Example of Increasing Usage of Silver and Silver Nanoparticles. Polymers 2011, 3, 340–366. [Google Scholar] [CrossRef]
  91. Qu, X.; Alvarez, P.J.; Li, Q. Applications of nanotechnology in water and wastewater treatment. Water Res. 2013, 47, 3931–3946. [Google Scholar] [CrossRef]
  92. Veerapandian, M.; Lim, S.K.; Nam, H.M.; Kuppannan, G.; Yun, K.S. Glucosamine-functionalized silver glyconanoparticles: Characterization and antibacterial activity. Anal. Bioanal. Chem. 2010, 398, 867–876. [Google Scholar] [CrossRef]
  93. Zare, B.; Faramarzi, M.A.; Sepehrizadeh, Z.; Shakibaie, M.; Rezaie, S.; Shahverdi, A.R. Biosynthesis and recovery of rod-shaped tellurium nanoparticles and their bactericidal activities. Mater. Res. Bull. 2012, 47, 3719–3725. [Google Scholar] [CrossRef]
  94. Webster, T.; Wang, Q.; Perez, J.M. Inhibited growth of Pseudomonas aeruginosa by dextran- and polyacrylic acid-coated ceria nanoparticles. Int. J. Nanomed. 2013, 8, 3395–3399. [Google Scholar] [CrossRef]
  95. Liu, Y.; He, L.; Mustapha, A.; Li, H.; Hu, Z.; Lin, M. Antibacterial activities of zinc oxide nanoparticles against Escherichia coli O157:H7. J. Appl. Microbiol. 2009, 107, 1193–1201. [Google Scholar] [CrossRef]
  96. Huang, Z.; Zheng, X.; Yan, D.; Yin, G.; Liao, X.; Kang, Y.; Yao, Y.; Huang, D.; Hao, B. Toxicological Effect of ZnO Nanoparticles Based on Bacteria. Langmuir 2008, 24, 4140–4144. [Google Scholar] [CrossRef]
  97. Kwak, S.-Y.; Kim, S.H.; Kim, S.S. Hybrid organic/inorganic reverse osmosis (RO) membrane for bactericidal anti-fouling. 1. Preparation and characterization of TiO2 nanoparticle self-assembled aromatic polyamide thin-film-composite (TFC) membrane. Environ. Sci. Technol. 2001, 35, 2388–2394. [Google Scholar] [CrossRef]
  98. Hernandez-Delgadillo, R.; Velasco-Arias, D.; Diaz, D.; Arevalo-Niño, K.; Garza-Enriquez, M.; De la Garza-Ramos, M.A.; Cabral-Romero, C. Zerovalent bismuth nanoparticles inhibit Streptococcus mutans growth and formation of biofilm. Int. J. Nanomed. 2012, 7, 2109–2113. [Google Scholar] [CrossRef]
  99. Karlsson, H.L.; Cronholm, P.; Gustafsson, J.; Möller, L. Copper Oxide Nanoparticles Are Highly Toxic: A Comparison between Metal Oxide Nanoparticles and Carbon Nanotubes. Chem. Res. Toxicol. 2008, 21, 1726–1732. [Google Scholar] [CrossRef]
  100. Lankveld, D.P.K.; Oomen, A.G.; Krystek, P.; Neigh, A.; De Jong, A.T.; Noorlander, C.W.; Van Eijkeren, J.; Geertsma, R.E.; De Jong, W.H. The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials 2010, 31, 8350–8361. [Google Scholar] [CrossRef]
  101. Qiu, Z.; Yu, Y.; Chen, Z.; Jin, M.; Yang, D.; Zhao, Z.; Wang, J.; Shen, Z.; Wang, X.; Qian, D.; et al. Nanoalumina promotes the horizontal transfer of multiresistance genes mediated by plasmids across genera. Proc. Natl. Acad. Sci. USA 2012, 109, 4944–4949. [Google Scholar] [CrossRef]
  102. Veerapandian, M.; Yun, K. Functionalization of biomolecules on nanoparticles: Specialized for antibacterial applications. Appl. Microbiol. Biotechnol. 2011, 90, 1655–1667. [Google Scholar] [CrossRef]
  103. Kotagiri, N.; Lee, J.S.; Kim, J.-W. Selective pathogen targeting and macrophage evading carbon nanotubes through dextran sulfate coating and PEGylation for photothermal theranostics. J. Biomed. Nanotechnol. 2013, 9, 1008–1016. [Google Scholar] [CrossRef]
  104. Kang, S.; Pinault, M.; Pfefferle, L.D.; Elimelech, M. Single-Walled Carbon Nanotubes Exhibit Strong Antimicrobial Activity. Langmuir 2007, 23, 8670–8673. [Google Scholar] [CrossRef] [PubMed]
  105. Xia, X.R.; Monteiro-Riviere, N.A.; Riviere, J.E. Intrinsic biological property of colloidal fullerene nanoparticles (nC60): Lack of lethality after high dose exposure to human epidermal and bacterial cells. Toxicol. Lett. 2010, 197, 128–134. [Google Scholar] [CrossRef] [PubMed]
  106. Rajesh, S.; Koshi, E.; Philip, K.; Mohan, A. Antimicrobial photodynamic therapy: An overview. J. Indian Soc. Periodontol. 2011, 15, 323–327. [Google Scholar] [CrossRef]
  107. Hancock, R.E.W.; Sahl, H.-G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 2006, 24, 1551–1557. [Google Scholar] [CrossRef]
  108. Peschel, A.; Sahl, H.-G. The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Genet. 2006, 4, 529–536. [Google Scholar] [CrossRef] [PubMed]
  109. Eby, D.M.; Farrington, K.E.; Johnson, G.R. Synthesis of Bioinorganic Antimicrobial Peptide Nanoparticles with Potential Therapeutic Properties. Biomacromolecules 2008, 9, 2487–2494. [Google Scholar] [CrossRef]
  110. Blin, T.; Purohit, V.; Leprince, J.; Jouenne, T.; Glinel, K. Bactericidal Microparticles Decorated by an Antimicrobial Peptide for the Easy Disinfection of Sensitive Aqueous Solutions. Biomacromolecules 2011, 12, 1259–1264. [Google Scholar] [CrossRef]
  111. Liu, L.; Xu, K.; Wang, H.; Jeremy Tan, P.; Fan, W.; Venkatraman, S.S.; Li, L.; Yang, Y.-Y. Self-assembled cationic peptide nanopar-ticles as an efficient antimicrobial agent. Nat. Nanotechnol. 2009, 4, 457–463. [Google Scholar] [CrossRef]
  112. Makovitzki, A.; Baram, J.; Shai, Y. Antimicrobial lipopolypeptides composed of palmitoyl di- and tricationic peptides: In vitro and in vivo activities, self-assembly to nanostructures, and a plausible mode of action. Biochemistry 2008, 47, 10630–10636. [Google Scholar] [CrossRef]
  113. Khara, J.S.; Wang, Y.; Ke, X.-Y.; Liu, S.; Newton, S.M.; Langford, P.R.; Yang, Y.Y.; Ee, P.L.R. Anti-mycobacterial activities of synthetic cationic α-helical peptides and their synergism with rifampicin. Biomaterials 2014, 35, 2032–2038. [Google Scholar] [CrossRef]
  114. Engler, A.C.; Wiradharma, N.; Ong, Z.Y.; Coady, D.J.; Hedrick, J.L.; Y. -Yang, Y. Emerging trends in macromolecular antimi-crobials to fight multi-drug-resistant infections. Nano Today 2012, 7, 201–222. [Google Scholar] [CrossRef]
  115. Song, J.; Kang, H.; Lee, C.; Hwang, S.H.; Jang, J. Aqueous Synthesis of Silver Nanoparticle Embedded Cationic Polymer Nanofibers and Their Antibacterial Activity. ACS Appl. Mater. Interfaces 2012, 4, 460–465. [Google Scholar] [CrossRef]
  116. Kong, M.; Chen, X.G.; Xing, K.; Park, H.J. Antimicrobial properties of chitosan and mode of action: A state of the art review. Int. J. Food Microbiol. 2010, 144, 51–63. [Google Scholar] [CrossRef]
  117. Qi, L.; Xu, Z.; Jiang, X.; Hu, C.; Zou, X. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydr. Res. 2004, 339, 2693–2700. [Google Scholar] [CrossRef]
  118. Rabea, E.I.; Badawy, M.E.-T.; Stevens, C.V.; Smagghe, G.; Steurbaut, W. Chitosan as Antimicrobial Agent: Applications and Mode of Action. Biomacromolecules 2003, 4, 1457–1465. [Google Scholar] [CrossRef]
  119. Friedman, A.J.; Phan, J.; Schairer, D.O.; Champer, J.; Qin, M.; Pirouz, A.; Blecher-Paz, K.; Oren, A.; Liu, P.T.; Modlin, R.L. Antimi-crobial and anti-inflammatory activity of chitosan–alginate nanoparticles: A targeted therapy for cutaneous pathogens. J. Investig. Dermatol. 2013, 133, 1231–1239. [Google Scholar] [CrossRef]
  120. Potara, M.; Jakab, E.; Damert, A.; Popescu, O.; Canpean, V.; Astilean, S. Synergistic antibacterial activity of chitosan–silver nanocomposites on Staphylococcus aureus. Nanotechnology 2011, 22, 135101. [Google Scholar] [CrossRef]
  121. Hosseinkhani, H.; Hong, P.-D.; Yu, D.-S. Self-Assembled Proteins and Peptides for Regenerative Medicine. Chem. Rev. 2013, 113, 4837–4861. [Google Scholar] [CrossRef]
  122. Elsabahy, M.; Heo, G.S.; Lim, S.-M.; Sun, G.; Wooley, K.L. Polymeric Nanostructures for Imaging and Therapy. Chem. Rev. 2015, 115, 10967–11011. [Google Scholar] [CrossRef]
  123. Jadidi, A.; Davoodian, F.; Salahinejad, E. Effect of poly lactic-co-glycolic acid encapsulation on drug delivery kinetics from vancomycin-impregnated Ca-Mg silicate scaffolds. Prog. Org. Coat. 2020, 149, 105970. [Google Scholar] [CrossRef]
  124. Jadidi, A.; Shokrgozar, M.A.; Sardari, S.; Maadani, A.M. Gefitinib-loaded polydopamine-coated hollow mesoporous silica nanoparticle for gastric cancer application. Int. J. Pharm. 2022, 629, 122342. [Google Scholar] [CrossRef] [PubMed]
  125. Kashkooli, F.M.; Soltani, M.; Momeni, M.M.; Rahmim, A. Enhanced Drug Delivery to Solid Tumors via Drug-Loaded Nanocarriers: An Image-Based Computational Framework. Front. Oncol. 2021, 11, 655781. [Google Scholar] [CrossRef]
  126. Kashkooli, F.M.; Rezaeian, M.; Soltani, M. Drug delivery through nanoparticles in solid tumors: A mechanistic understanding. Nanomedicine 2022, 17, 695–716. [Google Scholar] [CrossRef] [PubMed]
  127. Zhang, L.; Pornpattananangkul, D.; Hu, C.-M.; Huang, C.-M. Development of Nanoparticles for Antimicrobial Drug Delivery. Curr. Med. Chem. 2010, 17, 585–594. [Google Scholar] [CrossRef] [PubMed]
  128. Poole, K. Mechanisms of bacterial biocide and antibiotic resistance. J. Appl. Microbiol. 2002, 92, 55S–64S. [Google Scholar] [CrossRef]
  129. Goharshadi, E.K.; Goharshadi, K.; Moghayedi, M. The use of nanotechnology in the fight against viruses: A critical review. Co-Ord. Chem. Rev. 2022, 464, 214559. [Google Scholar] [CrossRef]
  130. De Siqueira, L.B.D.O.; Matos, A.P.D.S.; da Silva, M.R.M.; Pinto, S.R.; Santos-Oliveira, R.; Ricci-Júnior, E. Pharmaceutical nanotechnology applied to phthalocyanines for the promotion of antimicrobial photodynamic therapy: A literature review. Photodiagnosis Photodyn. Ther. 2022, 39, 102896. [Google Scholar] [CrossRef]
  131. Nicolosi, D.; Scalia, M.; Nicolosi, V.M.; Pignatello, R. Encapsulation in fusogenic liposomes broadens the spectrum of action of vancomycin against Gram-negative bacteria. Int. J. Antimicrob. Agents 2010, 35, 553–558. [Google Scholar] [CrossRef]
  132. Cheow, W.S.; Chang, M.W.; Hadinoto, K. The roles of lipid in anti-biofilm efficacy of lipid–polymer hybrid nanoparticles encapsulating antibiotics. Colloids Surf. A Physicochem. Eng. Asp. 2011, 389, 158–165. [Google Scholar] [CrossRef]
  133. Sanderson, N.M.; Guo, B.; Jacob, A.E.; Handley, P.S.; Cunniffe, J.G.; Jones, M.N. The interaction of cationic liposomes with the skin-associated bacterium Staphylococcus epidermidis: Effects of ionic strength and temperature. Biochim. Biophys. Acta Biomembr. 1996, 1283, 207–214. [Google Scholar] [CrossRef]
  134. Abed, N.; Couvreur, P. Nanocarriers for antibiotics: A promising solution to treat intracellular bacterial infections. Int. J. Antimicrob. Agents 2014, 43, 485–496. [Google Scholar] [CrossRef] [PubMed]
  135. Clemens, D.L.; Lee, B.-Y.; Xue, M.; Thomas, C.R.; Meng, H.; Ferris, D.; Nel, A.E.; Zink, J.I.; Horwitz, M.A. Targeted Intracellular Delivery of Antituberculosis Drugs to Mycobacterium tuberculosis-Infected Macrophages via Functionalized Mesoporous Silica Nanoparticles. Antimicrob. Agents Chemother. 2012, 56, 2535–2545. [Google Scholar] [CrossRef] [PubMed]
  136. Forier, K.; Raemdonck, K.; De Smedt, S.C.; Demeester, J.; Coenye, T.; Braeckmans, K. Lipid and polymer nanoparticles for drug delivery to bacterial biofilms. J. Control. Release 2014, 190, 607–623. [Google Scholar] [CrossRef] [PubMed]
  137. Pissuwan, D.; Cortie, C.H.; Valenzuela, S.M.; Cortie, M.B. Functionalised gold nanoparticles for controlling pathogenic bacteria. Trends Biotechnol. 2010, 28, 207–213. [Google Scholar] [CrossRef]
  138. Gu, H.; Ho, P.L.; Tong, E.; Wang, L.; Xu, B. Presenting Vancomycin on Nanoparticles to Enhance Antimicrobial Activities. Nano Lett. 2003, 3, 1261–1263. [Google Scholar] [CrossRef]
  139. Zhao, Y.; Tian, Y.; Cui, Y.; Liu, W.; Ma, W.; Jiang, X. Small Molecule-Capped Gold Nanoparticles as Potent Antibacterial Agents That Target Gram-Negative Bacteria. J. Am. Chem. Soc. 2010, 132, 12349–12356. [Google Scholar] [CrossRef]
  140. Schairer, D.O.; Chouake, J.S.; Nosanchuk, J.D.; Friedman, A.J. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 2012, 3, 271–279. [Google Scholar] [CrossRef]
  141. Privett, B.J.; Broadnax, A.D.; Bauman, S.J.; Riccio, D.A.; Schoenfisch, M.H. Examination of bacterial resistance to exogenous nitric oxide. Nitric Oxide 2012, 26, 169–173. [Google Scholar] [CrossRef]
  142. Pinto, R.V.; Carvalho, S.; Antunes, F.; Pires, J.; Pinto, M.L. Emerging Nitric Oxide and Hydrogen Sulfide Releasing Carriers for Skin Wound Healing Therapy. ChemMedChem 2021, 17, e202100429. [Google Scholar] [CrossRef]
  143. Afshari, A.R.; Sanati, M.; Mollazadeh, H.; Kesharwani, P.; Johnston, T.P.; Sahebkar, A. Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways. Semin. Cancer Biol. 2022, 86, 860–872. [Google Scholar] [CrossRef]
  144. Hetrick, E.M.; Shin, J.H.; Stasko, N.A.; Johnson, C.B.; Wespe, D.A.; Holmuhamedov, E.; Schoenfisch, M.H. Bactericidal Efficacy of Nitric Oxide-Releasing Silica Nanoparticles. ACS Nano 2008, 2, 235–246. [Google Scholar] [CrossRef]
  145. Lu, Y.; Slomberg, D.L.; Schoenfisch, M.H. Nitric oxide-releasing chitosan oligosaccharides as antibacterial agents. Biomaterials 2014, 35, 1716–1724. [Google Scholar] [CrossRef]
  146. Han, G.; Martinez, L.R.; Mihu, M.R.; Friedman, A.J.; Friedman, J.M.; Nosanchuk, J.D. Nitric Oxide Releasing Nanoparticles Are Therapeutic for Staphylococcus aureus Abscesses in a Murine Model of Infection. PLoS ONE 2009, 4, e7804. [Google Scholar] [CrossRef]
  147. Friedman, A.J.; Han, G.; Navati, M.S.; Chacko, M.; Gunther, L.; Alfieri, A.; Friedman, J.M. Sustained release nitric oxide releasing nanoparticles: Characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide 2008, 19, 12–20. [Google Scholar] [CrossRef]
  148. Martinez, L.R.; Han, G.; Chacko, M.; Mihu, M.R.; Jacobson, M.; Gialanella, P.; Friedman, A.J.; Nosanchuk, J.D.; Friedman, J.M. Antimicrobial and Healing Efficacy of Sustained Release Nitric Oxide Nanoparticles Against Staphylococcus aureus Skin Infection. J. Investig. Dermatol. 2009, 129, 2463–2469. [Google Scholar] [CrossRef]
  149. Chow, J.W.; Victor, L.Y. Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: A commentary. Int. J. Antimicrob. Agents 1999, 11, 7–12. [Google Scholar] [CrossRef]
  150. Toti, U.S.; Guru, B.R.; Hali, M.; McPharlin, C.M.; Wykes, S.M.; Panyam, J.; Whittum-Hudson, J.A. Targeted delivery of antibiotics to intracellular chlamydial infections using PLGA nanoparticles. Biomaterials 2011, 32, 6606–6613. [Google Scholar] [CrossRef]
  151. Carmona, D.; Lalueza, P.; Balas, F.; Arruebo, M.; Santamaría, J. Mesoporous silica loaded with peracetic acid and silver nano-particles as a dual-effect, highly efficient bactericidal agent. Microporous Mesoporous Mater. 2012, 161, 84–90. [Google Scholar] [CrossRef]
  152. Hurdle, J.G.; O’Neill, A.J.; Chopra, I.; Lee, R.E. Targeting bacterial membrane function: An underexploited mechanism for treating persistent infections. Nat. Rev. Microbiol. 2011, 9, 62–75. [Google Scholar] [CrossRef]
  153. Chono, S.; Tanino, T.; Seki, T.; Morimoto, K. Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections. J. Control. Release 2008, 127, 50–58. [Google Scholar] [CrossRef]
  154. Soltani, M.; Souri, M.; Moradi Kashkooli, F. Effects of hypoxia and nanocarrier size on pH-responsive nano-delivery system to solid tumors. Sci. Rep. 2021, 11, 19350. [Google Scholar] [CrossRef] [PubMed]
  155. Radovic-Moreno, A.F.; Lu, T.K.; Puscasu, V.A.; Yoon, C.J.; Langer, R.; Farokhzad, O.C. Surface charge-switching polymeric na-noparticles for bacterial cell wall-targeted delivery of antibiotics. ACS Nano 2012, 6, 4279–4287. [Google Scholar] [CrossRef] [PubMed]
  156. Pornpattananangkul, D.; Olson, S.; Aryal, S.; Sartor, M.; Huang, C.-M.; Vecchio, K.; Zhang, L. Stimuli-Responsive Liposome Fusion Mediated by Gold Nanoparticles. ACS Nano 2010, 4, 1935–1942. [Google Scholar] [CrossRef]
  157. Gao, W.; Vecchio, D.; Li, J.; Zhu, J.; Zhang, Q.; Fu, V.; Li, J.; Thamphiwatana, S.; Lu, D.; Zhang, L. Hydrogel containing nanoparti-cle-stabilized liposomes for topical antimicrobial delivery. Acs Nano 2014, 8, 2900–2907. [Google Scholar] [CrossRef] [PubMed]
  158. Pornpattananangkul, D.; Zhang, L.; Olson, S.; Aryal, S.; Obonyo, M.; Vecchio, K.; Huang, C.-M.; Zhang, L. Bacterial Toxin-Triggered Drug Release from Gold Nanoparticle-Stabilized Liposomes for the Treatment of Bacterial Infection. J. Am. Chem. Soc. 2011, 133, 4132–4139. [Google Scholar] [CrossRef]
  159. Xiong, M.-H.; Bao, Y.; Yang, X.-Z.; Wang, Y.-C.; Sun, B.; Wang, J. Lipase-sensitive polymeric triple-layered nanogel for “on-demand” drug delivery. J. Am. Chem. Soc. 2012, 134, 4355–4362. [Google Scholar] [CrossRef]
  160. Xiong, M.-H.; Li, Y.-J.; Bao, Y.; Yang, X.-Z.; Hu, B.; Wang, J. Bacteria-Responsive Multifunctional Nanogel for Targeted Antibiotic Delivery. Adv. Mater. 2012, 24, 6175–6180. [Google Scholar] [CrossRef]
  161. Shi, B.; Leung, D.Y.; Taylor, P.A.; Li, H. MRSA colonization is associated with decreased skin commensal bacteria in atopic dermatitis. J. Investig. Dermatol. 2018, 138, 1668. [Google Scholar] [CrossRef]
  162. Lu, B.; Ye, H.; Shang, S.; Xiong, Q.; Yu, K.; Li, Q.; Xiao, Y.; Dai, F.; Lan, G. Novel wound dressing with chitosan gold nanoparticles capped with a small molecule for effective treatment of multiantibiotic-resistant bacterial infections. Nanotechnology 2018, 29, 425603. [Google Scholar] [CrossRef]
  163. Liu, M.; He, D.; Yang, T.; Liu, W.; Mao, L.; Zhu, Y.; Wu, J.; Luo, G.; Deng, J. An efficient antimicrobial depot for infectious site-targeted chemo-photothermal therapy. J. Nanobiotechnol. 2018, 16, 23. [Google Scholar] [CrossRef]
  164. Alfatemi, S.H.; Rad, M.S.; Iriti, M. Antimicrobial synergic effect of allicin and silver nanoparticles on skin infection caused by methicillin-resistant Staphylococcus aureus spp. Ann. Med. Heath Sci. Res. 2014, 4, 863–868. [Google Scholar] [CrossRef]
  165. Ran, X.; Du, Y.; Wang, Z.; Wang, H.; Pu, F.; Ren, J.; Qu, X. Hyaluronic Acid-Templated Ag Nanoparticles/Graphene Oxide Composites for Synergistic Therapy of Bacteria Infection. ACS Appl. Mater. Interfaces 2017, 9, 19717–19724. [Google Scholar] [CrossRef]
  166. Ribeiro, K.L.; Frías, I.A.; Franco, O.L.; Dias, S.C.; Sousa-Junior, A.A.; Silva, O.N.; Bakuzis, A.F.; Oliveira, M.D.; Andrade, C.A. Clavanin A-bioconjugated Fe3O4/Silane core-shell nanoparticles for thermal ablation of bacterial biofilms. Colloids Surf. B Biointerfaces 2018, 169, 72–81. [Google Scholar] [CrossRef]
  167. Francolini, I.; Giansanti, L.; Piozzi, A.; Altieri, B.; Mauceri, A.; Mancini, G. Glucosylated liposomes as drug delivery systems of usnic acid to address bacterial infections. Colloids Surf. B Biointerfaces 2019, 181, 632–638. [Google Scholar] [CrossRef]
  168. Szaciłowski, K.; Macyk, W.; Stochel, G. Synthesis, structure and photoelectrochemical properties of the TiO2–Prussian blue nanocomposite. J. Mater. Chem. 2006, 16, 4603–4611. [Google Scholar] [CrossRef]
  169. Mir, M.; Ahmed, N.; Permana, A.D.; Rodgers, A.M.; Donnelly, R.F.; Rehman, A.U. Enhancement in site-specific delivery of car-vacrol against methicillin resistant Staphylococcus aureus induced skin infections using enzyme responsive nanoparticles: A proof of concept study. Pharmaceutics 2019, 11, 606. [Google Scholar] [CrossRef] [PubMed]
  170. Nostro, A.; Papalia, T. Antimicrobial Activity of Carvacrol: Current Progress and Future Prospectives. Recent Pat. Anti-Infect. Drug Discov. 2012, 7, 28–35. [Google Scholar] [CrossRef]
  171. Lange-Asschenfeldt, B.; Marenbach, D.; Lang, C.; Patzelt, A.; Ulrich, M.; Maltusch, A.; Terhorst, D.; Stockfleth, E.; Sterry, W.; Lademann, J. Distribution of Bacteria in the Epidermal Layers and Hair Follicles of the Human Skin. Ski. Pharmacol. Physiol. 2011, 24, 305–311. [Google Scholar] [CrossRef]
  172. Hsu, C.-Y.; Yang, S.-C.; Sung, C.T.; Weng, Y.-H.; Fang, J.-Y. Anti-MRSA malleable liposomes carrying chloramphenicol for ameliorating hair follicle targeting. Int. J. Nanomed. 2017, 12, 8227–8238. [Google Scholar] [CrossRef]
  173. Alalaiwe, A.; Wang, P.-W.; Lu, P.-L.; Chen, Y.-P.; Fang, J.-Y.; Yang, S.-C. Synergistic Anti-MRSA Activity of Cationic Nanostructured Lipid Carriers in Combination with Oxacillin for Cutaneous Application. Front. Microbiol. 2018, 9, 1493. [Google Scholar] [CrossRef]
  174. Yang, S.; Han, X.; Yang, Y.; Qiao, H.; Yu, Z.; Liu, Y.; Wang, J.; Tang, T. Bacteria-targeting nanoparticles with microenviron-ment-responsive antibiotic release to eliminate intracellular Staphylococcus aureus and associated infection. ACS Appl. Mater. Interfaces 2018, 10, 14299–14311. [Google Scholar] [CrossRef] [PubMed]
  175. Yang, S.-C.; Aljuffali, I.A.; Sung, C.T.; Lin, C.-F.; Fang, J.-Y. Antimicrobial activity of topically-applied soyaethyl morpholinium ethosulfate micelles against Staphylococcus species. Nanomedicine 2016, 11, 657–671. [Google Scholar] [CrossRef]
  176. Kang, X.-Q.; Shu, G.-F.; Jiang, S.-P.; Xu, X.-L.; Qi, J.; Jin, F.-Y.; Liu, D.; Xiao, Y.-H.; Lu, X.-Y.; Du, Y.-Z. Effective targeted therapy for drug-resistant infection by ICAM-1 antibody-conjugated TPGS modified β-Ga2O3: Cr3+ nanoparticles. Theranostics 2019, 9, 2739. [Google Scholar] [CrossRef]
  177. Wang, X.-S.; Situ, J.-Q.; Ying, X.-Y.; Chen, H.; Pan, H.-F.; Jin, Y.; Du, Y.-Z. β-Ga2O3:Cr3+ nanoparticle: A new platform with near infrared photoluminescence for drug targeting delivery and bio-imaging simultaneously. Acta Biomater. 2015, 22, 164–172. [Google Scholar] [CrossRef] [PubMed]
  178. Kłodzińska, S.N.; Priemel, P.A.; Rades, T.; Mørck Nielsen, H. Inhalable antimicrobials for treatment of bacterial bio-film-associated sinusitis in cystic fibrosis patients: Challenges and drug delivery approaches. Int. J. Mol. Sci. 2016, 17, 1688. [Google Scholar] [CrossRef]
  179. Deacon, J.; Abdelghany, S.M.; Quinn, D.J.; Schmid, D.; Megaw, J.; Donnelly, R.F.; Jones, D.S.; Kissenpfennig, A.; Elborn, J.S.; Gilmore, B.F.; et al. Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: Formulation, characterisation and functionalisation with dornase alfa (DNase). J. Control. Release 2015, 198, 55–61. [Google Scholar] [CrossRef]
  180. Casciaro, B.; D’Angelo, I.; Zhang, X.; Loffredo, M.R.; Conte, G.; Cappiello, F.; Quaglia, F.; Di, Y.-P.P.; Ungaro, F.; Mangoni, M.L. Poly(lactide-co-glycolide) Nanoparticles for Prolonged Therapeutic Efficacy of Esculentin-1a-Derived Antimicrobial Peptides against Pseudomonas aeruginosa Lung Infection: In Vitro and in Vivo Studies. Biomacromolecules 2019, 20, 1876–1888. [Google Scholar] [CrossRef]
  181. Chen, M.; Xie, S.; Wei, J.; Song, X.; Ding, Z.; Li, X. Antibacterial micelles with vancomycin-mediated targeting and pH/lipase-triggered release of antibiotics. ACS Appl. Mater. Interfaces 2018, 10, 36814–36823. [Google Scholar] [CrossRef]
  182. Wang, Y.; Yuan, Q.; Feng, W.; Pu, W.; Ding, J.; Zhang, H.; Li, X.; Yang, B.; Dai, Q.; Cheng, L.; et al. Targeted delivery of antibiotics to the infected pulmonary tissues using ROS-responsive nanoparticles. J. Nanobiotechnol. 2019, 17, 1–16. [Google Scholar] [CrossRef]
  183. Hsu, C.-Y.; Sung, C.T.; Aljuffali, I.A.; Chen, C.-H.; Hu, K.-Y.; Fang, J.-Y. Intravenous anti-MRSA phosphatiosomes mediate en-hanced affinity to pulmonary surfactants for effective treatment of infectious pneumonia. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 215–225. [Google Scholar] [CrossRef]
  184. Tenland, E.; Pochert, A.; Krishnan, N.; Umashankar Rao, K.; Kalsum, S.; Braun, K.; Glegola-Madejska, I.; Lerm, M.; Robertson, B.D.; Lindén, M. Effective delivery of the anti-mycobacterial peptide NZX in mesoporous silica nanoparticles. PLoS ONE 2019, 14, e0212858. [Google Scholar] [CrossRef] [PubMed]
  185. Hussain, S.; Joo, J.; Kang, J.; Kim, B.; Braun, G.B.; She, Z.-G.; Kim, D.; Mann, A.P.; Mölder, T.; Teesalu, T. Antibiotic-loaded nano-particles targeted to the site of infection enhance antibacterial efficacy. Nat. Biomed. Eng. 2018, 2, 95–103. [Google Scholar] [CrossRef]
  186. Zhao, G.; Chen, Y.; He, Y.; Chen, F.; Gong, Y.; Chen, S.; Xu, Y.; Su, Y.; Wang, C.; Wang, J. Succinylated casein-coated pep-tide-mesoporous silica nanoparticles as an antibiotic against intestinal bacterial infection. Biomater. Sci. 2019, 7, 2440–2451. [Google Scholar] [CrossRef]
  187. Calabrese, I.; Cavallaro, G.; Scialabba, C.; Licciardi, M.; Merli, M.; Sciascia, L.; Liveri, M.L.T. Montmorillonite nanodevices for the colon metronidazole delivery. Int. J. Pharm. 2013, 457, 224–236. [Google Scholar] [CrossRef]
  188. Ping, Y.; Hu, X.; Yao, Q.; Hu, Q.; Amini, S.; Miserez, A.; Tang, G. Engineering bioinspired bacteria-adhesive clay nanoparticles with a membrane-disruptive property for the treatment of Helicobacter pylori infection. Nanoscale 2016, 8, 16486–16498. [Google Scholar] [CrossRef]
  189. Angsantikul, P.; Thamphiwatana, S.; Zhang, Q.; Spiekermann, K.; Zhuang, J.; Fang, R.H.; Gao, W.; Obonyo, M.; Zhang, L. Coating Nanoparticles with Gastric Epithelial Cell Membrane for Targeted Antibiotic Delivery against Helicobacter pylori Infection. Adv. Ther. 2018, 1, 1800016. [Google Scholar] [CrossRef]
  190. Huttunen, R.; Aittoniemi, J. New concepts in the pathogenesis, diagnosis and treatment of bacteremia and sepsis. J. Infect. 2011, 63, 407–419. [Google Scholar] [CrossRef]
  191. Rai, A.; Pinto, S.; Velho, T.R.; Ferreira, A.F.; Moita, C.; Trivedi, U.; Evangelista, M.; Comune, M.; Rumbaugh, K.P.; Simões, P.N.; et al. One-step synthesis of high-density peptide-conjugated gold nanoparticles with antimicrobial efficacy in a systemic infection model. Biomaterials 2016, 85, 99–110. [Google Scholar] [CrossRef]
  192. Qadri, S.; Haik, Y.; Mensah-Brown, E.; Bashir, G.; Fernandez-Cabezudo, M.J.; Al-Ramadi, B.K. Metallic nanoparticles to eradicate bacterial bone infection. Nanomed. Nanotechnol. Biol. Med. 2017, 13, 2241–2250. [Google Scholar] [CrossRef]
  193. Prasai, D.; Tuberquia, J.C.; Harl, R.R.; Jennings, G.K.; Bolotin, K.I. Graphene: Corrosion-Inhibiting Coating. ACS Nano 2012, 6, 1102–1108. [Google Scholar] [CrossRef]
  194. Fang, C.-H.; Tsai, P.-I.; Huang, S.-W.; Sun, J.-S.; Chang, J.Z.-C.; Shen, H.-H.; Chen, S.-Y.; Lin, F.H.; Hsu, L.-T.; Chen, Y.-C. Magnetic hyperthermia enhance the treatment efficacy of peri-implant osteomyelitis. BMC Infect. Dis. 2017, 17, 516. [Google Scholar] [CrossRef] [PubMed]
  195. Król, A.; Pomastowski, P.; Rafińska, K.; Railean-Plugaru, V.; Buszewski, B. Zinc oxide nanoparticles: Synthesis, antiseptic activity and toxicity mechanism. Adv. Colloid Interface Sci. 2017, 249, 37–52. [Google Scholar] [CrossRef]
  196. Bai, X.; Li, L.; Liu, H.; Tan, L.; Liu, T.; Meng, X. Solvothermal Synthesis of ZnO Nanoparticles and Anti-Infection Application in Vivo. ACS Appl. Mater. Interfaces 2015, 7, 1308–1317. [Google Scholar] [CrossRef] [PubMed]
  197. Haworth, C.S.; Bilton, D.; Chalmers, J.D.; Davis, A.M.; Froehlich, J.; Gonda, I.; Thompson, B.; Wanner, A.; O’Donnell, A.E. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): Two phase 3, randomised controlled trials. Lancet Respir. Med. 2019, 7, 213–226. [Google Scholar] [CrossRef] [PubMed]
  198. Eleraky, N.E.; Allam, A.; Hassan, S.B.; Omar, M.M. Nanomedicine Fight against Antibacterial Resistance: An Overview of the Recent Pharmaceutical Innovations. Pharmaceutics 2020, 12, 142. [Google Scholar] [CrossRef]
  199. ClinicalTrials.gov. Liposomal Amikacin for Inhalation (LAI) for Nontuberculous Mycobacteria. Available online: https://clinicaltrials.gov/ct2/show/NCT01315236 (accessed on 4 November 2019).
  200. ClinicalTrials.gov. Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKAYCE™)—Extension Phase. Available online: https://www.clinicaltrials.gov/ct2/show/NCT03905642 (accessed on 18 November 2019).
  201. ClinicalTrials.gov. Liposomal Amikacin for Inhalation (LAI) in the Treatment of Mycobacterium Abscessus Lung Disease. Available online: https://clinicaltrials.gov/ct2/show/NCT03038178 (accessed on 4 November 2019).
  202. ClinicalTrials.gov. Extension Study of Liposomal Amikacin for Inhalation in Cystic Fibrosis (CF) Patients with Chronic Pseudomonas Aeruginosa (Pa) Infection. Available online: https://clinicaltrials.gov/ct2/show/NCT01316276 (accessed on 12 November 2019).
  203. Mullard, A. FDA approves antitoxin antibody. Nat. Rev. Drug Discov. 2016, 15, 811–812. [Google Scholar] [CrossRef]
  204. Azeredo da Silveira, S.; Perez, A. Improving the fate of severely infected patients: The promise of anti-toxin treatments and superiority trials. Expert Rev. Anti-Infect. Ther. 2017, 15, 973–975. [Google Scholar] [CrossRef]
  205. Laterre, P.-F.; Colin, G.; Dequin, P.-F.; Dugernier, T.; Boulain, T.; da Silveira, S.A.; Lajaunias, F.; Perez, A.; François, B. CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: A first-in-human, double-blind, placebo-controlled, ran-domised trial. Lancet Infect. Dis. 2019, 19, 620–630. [Google Scholar] [CrossRef]
  206. Molchanova, N.; Hansen, P.R.; Franzyk, H. Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs. Molecules 2017, 22, 1430. [Google Scholar] [CrossRef]
  207. Stevens, D.A. Overview of amphotericin B colloidal dispersion (Amphocil). J. Infect. 1994, 28, 45–49. [Google Scholar] [CrossRef]
  208. Boswell, G.W.; Buell, D.; Bekersky, I. AmBisome (liposomal amphotericin B): A comparative review. J. Clin. Pharmacol. 1998, 38, 583–592. [Google Scholar] [CrossRef]
  209. Paterson, D.L.; David, K.; Mrsic, M.; Cetkovsky, P.; Weng, X.-H.; Sterba, J.; Krivan, G.; Boskovic, D.; Lu, M.; Zhu, L.-P. Pre-medication practices and incidence of infusion-related reactions in patients receiving AMPHOTEC®: Data from the Patient Registry of Amphotericin B Cholesteryl Sulfate Complex for Injection Clinical Tolerability (PRoACT) registry. J. Antimicrob. Chemother. 2008, 62, 1392–1400. [Google Scholar] [CrossRef]
  210. Jadhav, M.; Bamba, A.; Shinde, V.; Gogtay, N.; Kshirsagar, N.; Bichile, L.; Mathai, D.; Sharma, A.; Varma, S.; Digumarathi, R. Liposomal amphotericin B (Fungisome TM) for the treatment of cryptococcal meningitis in HIV/AIDS patients in India: A mul-ticentric, randomized controlled trial. J. Postgrad. Med. 2010, 56, 71. [Google Scholar] [CrossRef]
  211. Bruinenberg, P.; Blanchard, J.D.; Cipolla, D.C.; Dayton, F.; Mudumba, S.; Gonda, I. Inhaled liposomal ciprofloxacin: Once a day management of respiratory infections. In Respiratory Drug Delivery; Davis Healthcare International Publishing: Orlando, FL, USA, 2010; pp. 73–82. [Google Scholar]
  212. ClinicalTrials.gov. Phase 3 Study with Ciprofloxacin Dispersion for Inhalation in Non-CF Bronchiectasis (ORBIT-3). Available online: https://clinicaltrials.gov/ct2/show/NCT01515007 (accessed on 21 November 2019).
  213. ClinicalTrials.gov. Study to Evaluate Efficacy of LAI When Added to Multi-drug Regimen Compared to Multi-drug Regimen Alone (CONVERT). Available online: https://clinicaltrials.gov/ct2/show/NCT02344004 (accessed on 25 October 2019).
  214. ClinicalTrials.gov. Study of the Clinical Effectiveness of a Human Monoclonal Antibody to C. Difficile Toxin A and Toxin B in Patients with Clostridium Difficile Associated Disease. Available online: https://clinicaltrials.gov/ct2/show/NCT00350298?term=anti+toxin&draw=3&rank=13 (accessed on 16 November 2019).
  215. Crowther, G.S.; Baines, S.D.; Todhunter, S.L.; Freeman, J.; Chilton, C.H.; Wilcox, M.H. Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection. J. Antimicrob. Chemother. 2013, 68, 168–176. [Google Scholar] [CrossRef]
  216. Van der Velden, W.J.; van Iersel, T.M.; Blijlevens, N.; Donnelly, J.P. Safety and tolerability of the antimicrobial peptide human lactoferrin 1-11 (hLF1-11). BMC Med. 2009, 7, 44. [Google Scholar] [CrossRef]
  217. Zhang, W.; Li, Y.; Qian, G.; Wang, Y.; Chen, H.; Li, Y.-Z.; Liu, F.; Shen, Y.; Du, L. Identification and characterization of the an-ti-methicillin-resistant Staphylococcus aureus WAP-8294A2 biosynthetic gene cluster from Lysobacter enzymogenes OH11. Antimicrob. Agents Chemother. 2011, 55, 5581–5589. [Google Scholar] [CrossRef]
  218. Kaplan, C.W.; Sim, J.H.; Shah, K.R.; Kolesnikova-Kaplan, A.; Shi, W.; Eckert, R. Selective Membrane Disruption: Mode of Action of C16G2, a Specifically Targeted Antimicrobial Peptide. Antimicrob. Agents Chemother. 2011, 55, 3446–3452. [Google Scholar] [CrossRef]
  219. ClinicalTrials.gov. A Study of DPK-060 to Investigate Clinical Safety and Efficacy in Patients with Acute External Otitis. Available online: https://clinicaltrials.gov/ct2/show/NCT01447017 (accessed on 10 December 2019).
  220. Nilsson, A.C.; Janson, H.; Wold, H.; Fugelli, A.; Andersson, K.; Håkangård, C.; Olsson, P.; Olsen, W.M. LTX-109 Is a Novel Agent for Nasal Decolonization of Methicillin-Resistant and -Sensitive Staphylococcus aureus. Antimicrob. Agents Chemother. 2015, 59, 145–151. [Google Scholar] [CrossRef]
  221. Knight-Connoni, V.; Mascio, C.; Chesnel, L.; Silverman, J. Discovery and development of surotomycin for the treatment of Clostridium difficile. J. Ind. Microbiol. Biotechnol. 2016, 43, 195–204. [Google Scholar] [CrossRef]
  222. Stiefel, U.; Pultz, N.J.; Helfand, M.S.; Donskey, C.J. Efficacy of Oral Ramoplanin for Inhibition of Intestinal Colonization by Vancomycin-Resistant Enterococci in Mice. Antimicrob. Agents Chemother. 2004, 48, 2144–2148. [Google Scholar] [CrossRef]
Figure 1. Applications of nanomedicine in the treatment of infectious diseases caused by microbes. Reproduced with permission from [24]. Copyright Elsevier, 2014.
Figure 1. Applications of nanomedicine in the treatment of infectious diseases caused by microbes. Reproduced with permission from [24]. Copyright Elsevier, 2014.
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Figure 2. Immune response induction and how nanoparticles affect it [30]. Reproduced with permission from [30]. Copyright Springer, Nature, 2013.
Figure 2. Immune response induction and how nanoparticles affect it [30]. Reproduced with permission from [30]. Copyright Springer, Nature, 2013.
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Figure 3. (A) Candida T2MR assay process. (B) T2MR detecting particle reagent schematic. SPIONs covalently conjugate oligonucleotide probes. Each target had two nanoparticle populations with a target-complementary probe. These nanoparticles aggregate when hybridized to the target strand amplified in excess by asymmetric PCR, changing the sample’s T2MR signal. DNA concentration increases clustering. Reproduced with permission from [59]. Copyright Elsevier, 2017.
Figure 3. (A) Candida T2MR assay process. (B) T2MR detecting particle reagent schematic. SPIONs covalently conjugate oligonucleotide probes. Each target had two nanoparticle populations with a target-complementary probe. These nanoparticles aggregate when hybridized to the target strand amplified in excess by asymmetric PCR, changing the sample’s T2MR signal. DNA concentration increases clustering. Reproduced with permission from [59]. Copyright Elsevier, 2017.
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Figure 4. Assay using bio-barcodes for the detection of DNA and proteins. A representation in schematic form of (a) the identification of proteins by the use of the bio-barcode test; (b) detection of nucleic acids by the use of the bio-barcode test; as well as (c) the econometric detection method. Reproduced with permission from [24]. Copyright Elsevier, 2014.
Figure 4. Assay using bio-barcodes for the detection of DNA and proteins. A representation in schematic form of (a) the identification of proteins by the use of the bio-barcode test; (b) detection of nucleic acids by the use of the bio-barcode test; as well as (c) the econometric detection method. Reproduced with permission from [24]. Copyright Elsevier, 2014.
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Figure 5. Antimicrobial nanomaterials and nanoparticle-based drug delivery systems: A schematic overview.
Figure 5. Antimicrobial nanomaterials and nanoparticle-based drug delivery systems: A schematic overview.
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Figure 7. (A) Schematic of the nanoparticle-mediated drug targeting bacterial cell walls. A small negative charge and surface PEGylation prevent nanoparticles from attaching to nontarget cells or blood components at physiologic pH 7.4. The surface-charge-switching process activates at weakly acidic infection sites, attaching nanoparticles to negatively charged bacteria. (B) PLGA—PLH—PEG nanoparticles convert from anionic to cationic when the pH drops. (C) Minimum inhibitory concentrations (MIC) of S. aureus vancomycin formulation. * indicates p < 0.05. Reproduced with permission from [155]. Copyright American Chemical Society, 2012.
Figure 7. (A) Schematic of the nanoparticle-mediated drug targeting bacterial cell walls. A small negative charge and surface PEGylation prevent nanoparticles from attaching to nontarget cells or blood components at physiologic pH 7.4. The surface-charge-switching process activates at weakly acidic infection sites, attaching nanoparticles to negatively charged bacteria. (B) PLGA—PLH—PEG nanoparticles convert from anionic to cationic when the pH drops. (C) Minimum inhibitory concentrations (MIC) of S. aureus vancomycin formulation. * indicates p < 0.05. Reproduced with permission from [155]. Copyright American Chemical Society, 2012.
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Mehrabi, M.R.; Soltani, M.; Chiani, M.; Raahemifar, K.; Farhangi, A. Nanomedicine: New Frontiers in Fighting Microbial Infections. Nanomaterials 2023, 13, 483. https://doi.org/10.3390/nano13030483

AMA Style

Mehrabi MR, Soltani M, Chiani M, Raahemifar K, Farhangi A. Nanomedicine: New Frontiers in Fighting Microbial Infections. Nanomaterials. 2023; 13(3):483. https://doi.org/10.3390/nano13030483

Chicago/Turabian Style

Mehrabi, Mohammad Reza, Madjid Soltani, Mohsen Chiani, Kaamran Raahemifar, and Ali Farhangi. 2023. "Nanomedicine: New Frontiers in Fighting Microbial Infections" Nanomaterials 13, no. 3: 483. https://doi.org/10.3390/nano13030483

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