Application of Nanotechnology in Immunity against Infection

Abstract

The immune system has a physiological defense function, protecting the body from infectious diseases. Antibiotics have long been one of the most important means to treat infectious diseases, but in recent years, with the emergence of more and more multidrug-resistant (MDR) bacteria, it has become urgent to find new ways or drugs to treat infectious diseases. Nanoparticles (NPs) have attracted extensive attention owing to the special properties within the particle size range of 1–100 nanometers. In addition, NPs also have special shape symmetry and relative structural stability. The emergence of nanotechnology has brought new light to the widespread existence of MDR by its different antibacterial mechanisms. In addition to antibiotic nanocarriers being able to improve the antibacterial effect of antibiotics, some NPs also have certain antibacterial effect. What is more interesting is that linking functional groups on the surface of NPS as coatings can improve the stability of the whole system and improve the biocompatibility. The present review overviews the development of antimicrobial agents, so as to better understand the causes and mechanisms of antibiotic resistance in most microbial species, and to better think and explore new strategies to solve the problem. At the same time, this review introduces how nanotechnology can be applied to anti-infection immunity and its practical application and advantages in the treatment of infection.

1. Introduction

Nanotechnology is a technology capable of manipulating and controlling matter in the range of 1–100 nanometers [1]. Nanoparticles (NPs) refer to zero-dimensional, one-dimensional and two-dimensional materials with small size effect composed of ultrafine particles smaller than 100 nm, or three-dimensional materials with their unit structure. As early as 1959, the famous American physicist Richard P. Feynman mentioned in his speech “There’s Plenty of Room at the Bottom: An Invitation to Enter a New Field of Physics” that matter can be assembled by individual molecules or even atoms to meet requirements, heralding the beginning of nanotechnology [2]. This brilliant conjecture heralded the new age of nanotechnology, which gave us thorough and inexpensive control of the structure of matter. In 1986, K. Eric-Drexler published a monograph called Engines of Creation: The Coming Era of Nanotechnology, which brought nanotechnology into research focus and established the revolutionary new field of nanotechnology [3]. The prediction and analysis in these works have been proved and applied in recent years.

The development of nanotechnology has greatly promoted the development and progress of various disciplines and has important applications in different disciplines. Nanotechnology has applications in cell biology, where it can mimic the complex extracellular environment in vivo and dynamically monitor complex biological processes in real time at the single-cell level [4]. Nanotechnology also has great potential in the field of medicine. Its main applications include the use of NPs in disease diagnosis and pathogen screening, DNA sequencing, tumor detection imaging and gene therapy [5]: such as fluorescent NPs or dyed NPs which, since they almost do not interact with cellular proteins and optical properties, are not affected by the outer proteins; and charged NPs’ surface and surface chemical properties making it easier to internalize into cells and tissues compared with common molecular probes; and more importantly, NPs produced by fluorescence detection results are similar in the experiments in vivo and in vitro data, having good stability and reference: all of these advantages give NPs a very high application prospect and application value for imaging materials [6]. Nanotechnology also has wide applications in manufacturing. For example, NPs can be assembled on the surface of traditional textile materials, which can change the color of the fabric and even give the fabric some antimicrobial properties [7]. In addition, studies have confirmed that nano-silver layered dihydroxide (Ag-LDH) coating can be coated on the surface of metal, ceramic, glass and other different types of substrates, and Ag-LDH coating shows excellent and lasting antibacterial activity against both Gram-negative and Gram-positive bacteria [8]. Meanwhile, in medical immunology, NPs can be used as an immune adjuvant to stimulate the immune response of the body or as a carrier of entrap antigen for targeted delivery and activation induction. The application of nanotechnology in pharmacy is more remarkable. On the one hand, some NPs have their own medicinal effects. For example, metal or metal oxide NPs have a bactericidal effect and can be used as a bactericide. At the same time, the surface coating of NPs can be used to target the NPs, so as to improve the efficacy and reduce the toxic and side effects of drugs. NPs are often coated with functional chemical groups to achieve better stability, biocompatibility and active targeting [9]. On the other hand, NPs can be used as a drug carrier to control the release rate while maintaining the slow and lasting release of drugs, so as to reduce the frequency of drug use. The use of NPs loaded drugs can improve drug solubility.

With the industrialization of antibiotics, infectious diseases have gone from being untreatable and deadly to being curable and low-risk. However, the indiscriminate use of antibiotics has led to widespread antibiotic resistance and even the emergence of multidrug-resistance (MDR) in some bacteria. According to relevant statistics, bacterial resistance relates to all currently known natural or synthetic antimicrobial agents [10]. Faced with a serious situation, new methods, strategies or drugs continue to be found to remedy the situation. Otherwise, as bacterial resistance becomes more and more severe, once a serious bacterial infection occurs, there is nothing to do and infectious diseases will become highly lethal again, which will seriously threaten the lives and health of the public around the world. In the past few years, however, few new antibiotics have been discovered owing to the high cost and complexity of drug development [11]. Therefore, it is a wise choice to turn to the use of new technology to change the physical and chemical characteristics of existing antibiotics to change the way drugs work, so as to effectively solve MDR.

The special size, properties and high specific surface area characteristics of NPs have unsurpassable advantages in antibacterial and anti-MDR. Studies have shown that naked NPs (NPs without any surface modification) have a relatively fragile inner shell structure, which can be easily degraded and destroyed by the physiological environment in vivo in the actual physiological experiments. Adding a surface coating to the naked NPs can greatly improve stability, and the use of coated NPs-loaded antimicrobials can prevent unnecessary interactions and drug degradation before reaching the target tissue or cell, and maintain drug stability. More importantly, NPs can target diversity by changing their surface coating. According to the specific target, the chemical groups connected on the surface of NPs are changed so that the NPs can accurately identify the specific targeted therapeutic site. After reaching the specified site, the treatment effect is achieved by the sustained release of antibiotics. Meanwhile, nanotechnology can be used to optimize the physical and chemical characteristics of drugs, change the way of drug administration and reduce the discomfort of patients. What is more special is that NPs can wrap different antibiotics in the same nanocarrier [12]. As is well-known in the treatment of infectious diseases, a combination of multiple antibiotics is usually used to give faster action while reducing the side effects of the drugs. NPs not only have a killing effect on MDR bacteria themselves, but also can be used as an auxiliary agent, together with antibiotics to which microbes have developed resistance, to enhance the antibacterial capacity. They helped restore the antibacterial activity of older antibiotics to which microbes had developed resistance [6]. Therefore, nanotechnology has high prospects in the treatment of infectious diseases, and it has become a current research focus. Thousands of studies and papers have been published. However, due to the side effect of NPs, their application in the human body is limited. At present, there are few researches on the pharmacokinetics of NPs in the human body, and there are still some disputes about how NPs are absorbed, diffused, metabolized and their toxic and side effects after entering the human body, which needs further exploration and research.

This review is based on the actual existence of severe bacterial resistance and the lack of new antibiotics, combined with nanotechnology, known as one of the breakthrough technologies in the 21st century, to consider the combination of the two to alleviate the widespread bacterial resistance problem in the world. Relying on the national agricultural information system and the web of science database, we referred to a large number of literature, including on the composition and classification of bacteria, antibiotics antibacterial principle, the mechanism of bacterial resistance, the special advantage of nanotechnology, the classification of NPs, the application of nanotechnology in antibacterial immunity in as many as hundreds of articles. After careful classification and screening, seventy-eight articles were cited as theoretical support to emphasize the application of nanotechnology in anti-infection immunity and how it provides a new perspective for MDR (Figure 1).

2. Current Situation of Antimicrobial Application

The immune system has a physiological defense function, which can resist the invasion of pathogens and eliminate the invading pathogens and their harmful metabolites; that is, anti-infection immunity. Abnormal increase of physiological defense response may lead to hypersensitivity reaction, while too low or deficient response may lead to immunodeficiency disease or high susceptibility to pathogens. After the invasion of pathogenic bacteria, taking antibacterial or antiviral drugs mobilizes the whole immune system, including a variety of immune organs and immune cells to kill pathogens, to maintain the normal operation of life activities. Antimicrobials can inhibit or kill bacteria and be used to prevent and treat bacterial infections, including synthetic antimicrobials (such as sulfonamides, furans, quinolones, etc.) and antibiotics (such as streptomycin, cephalosporins, penicillin, etc.). Antibiotics are metabolites of microorganisms (bacteria, fungi and actinomycetes), which can kill or inhibit other pathogenic microorganisms at a certain concentration. British bacteriologist Alexander Fleming first discovered penicillin in 1928. After further research and improvement, penicillin was successfully applied to treat the human body’s anti-infection treatment. Since the discovery of penicillin, human beings have found it a powerful bactericidal drug, ending the era of almost untreatable infectious diseases. Since then, the search for new antibiotics has reached a climax, and the human race has entered a new era of synthetic new drugs. Infectious diseases pose less threat to human health and are easy to be cured.

However, with the increasing application of antibacterial drugs in clinical practice, some patients do not strictly follow the prescribed way of medication and arbitrarily change the frequency and time of medication, or stop the drug without authorization. Meanwhile, there are some patients who lack awareness of correct medication, treat antibiotics as a “panacea” and abuse them when encountering common cold fever and even non-infectious inflammation antibiotics. Related studies have shown that 90% of colds are caused by viral infections, so for most colds, antibacterials do not work but cause abuse of antibiotics. At the same time, the abuse of broad-spectrum antibiotics further aggravates the resistance of bacteria. Under normal circumstances, the human body’s oral cavity, respiratory tract and intestinal bacteria are parasitic flora with mutual restriction to maintain the balance state. If broad-spectrum antibiotics are used for a long period of time, the sensitive bacteria will be killed, while the insensitive bacteria will take the opportunity to reproduce [13].

Relevant World Health Organization (WHO) reports show that after the elimination of antibacterial drugs by a human or animal, the drug residues fermented in the soil and contaminated wastewater will enter the soil and water, leading to the development of drug resistance in the soil and water bacteria, and resistant components and genes will continue to occur with horizontal and vertical transmission. This could lead to bacterial resistance on a global scale. Antibacterial drugs have become less effective or even ineffective owing extensive abuse in human. According to a World Health Organization, Escherichia coli, klebsiella pneumoniae and staphylococcus aureus are more than 50% resistant to common antibiotics. The relevant research statistics show klebsiella pneumoniae resistance to carbapenems as being as high as 54% [14]. As a result, infectious diseases remain one of the world’s biggest health challenges; they may become a lethal disease, as bacteria develop resistance to many common antimicrobials.

The problem of antibiotics fighting pathogens is the underlying reason why most drugs are now resistant. Antimicrobial resistance in pathogens has different mechanisms, including chromosomal mutations, changes in membrane permeability, development of efflux pumps that expel multiple kinds of antibiotics, activation of enzymes that degraded the antibiotic, increased intracellular life cycle [15]. One of the most important things is that pathogens not only exist in the cytosol, but also in the organelles and even in the nucleus [16]. However, most antibiotics cannot penetrate the host cell and enter the cell, and only stay outside the cell; meanwhile, they will be degraded quickly before they are exposed to the pathogen or will not reach the effective therapeutic dose after exposure to the pathogen [17].

Antibiotics kill bacteria and also cause damage to the body. Drug resistance increases the dose of antibiotics, often producing toxic side effects. Quinolones, for example, can cause cartilage damage in young animals and joint pain and inflammation in a small number of patients. Tetracycline makes children’s teeth yellow. Rifampicin and erythromycin can cause liver damage. Chloramphenicol is difficult to inactivate after taking, can cause cardiovascular failure in children, “gray baby syndrome”, and serious cases can be fatal. Penicillin can cause anaphylactic shock, which can be life-threatening. The problems now facing the use of antimicrobial drugs to treat infectious diseases include not only bacterial resistance, but also the unbearable side effects of increased drug dosage or frequency in order to be effective. Therefore, it has become an urgent matter to find an effective solution.

3. Nanotechnology and Anti-Infection Immunity

While looking for new antimicrobial drugs, scientists envision the use of new techniques to modify the way antibiotics act, drug dosage forms, particle sizes, and so on to promote the bactericidal effect. Several types of antibacterial NPs and nano-antibiotic carriers have been shown to be effective in treating infectious diseases, including in drug-resistant ones, in vitro and in animal models [18]. The applications of nanotechnology in anti-infection immunity mainly include the direct bactericidal effect of some NPs [19]; the loading of antibiotics by nanocarriers, particularly in overcoming antibiotic-resistant pathogens, have been explored as a promising alternative to current antibiotic-based approaches [20].

3.1. Antibacterial NPs

NPs provide a new strategy for dealing with MDR bacteria. Recent studies have shown that some metal (e.g., silver [21], golds [22]) and metallic oxide nanostructures are known to have antibacterial activity and can be used to control infectious disease. Inorganic fungicides such as metal oxide NPs can destroy bacteria locally without causing toxicity to surrounding tissues [23]. Experiments have shown that zinc oxide (ZnO) NPs [24] and iron oxide (Fe₃O₄) NPs [25] have excellent antibacterial effects, although the antibacterial mechanism of some NPs is still unclear, and it is worth noting that these antibacterial effects can only occur in the range of nanoscale [26]. Among them, the main mechanism of the cytotoxicity of zinc oxide NPs may be mediated by inducing the production of reactive oxygen species (ROS) responsible for inducing apoptosis, and zinc oxide NPs induce toxicity in a cell-specific and proliferation-dependent manner [27]. The antibacterial mechanisms of other metal oxide NPs are not fully understood. Some metal oxide NPs exhibit a bactericidal effect, destroying the cell membrane of bacteria, usually associated with their physical structure and metal ion release [28]. Different researchers have given different explanations for the mechanism of NPs. Mritunjal Singh et al. believe that the main mechanism by which AgNPs exhibit antibacterial properties is to induce cell death by anchoring and penetrating the bacterial cell wall and damaging the outer membrane barrier components, such as liposolysaccharide or pore proteins [29], resulting in increased bacterial cell membrane permeability. In addition, metal NPs have an affinity to interact with biological materials containing sulfur and phosphorus in the bacterial cell; for example, AgNPs can interact with phosphorous compounds such as sulfur-containing proteins and DNA in bacterial membranes; therefore, metal NPs can act on bases to destroy DNA and cause cell death [30]. Yan Cui et al. speculated that the antibacterial effect of AuNPs is mainly through two ways: one is to change the membrane potential, inhibit the activity of ATP synthase, reduce the level of ATP; the other is to inhibit the binding of ribosomal subunits to tRNA, through the above two kinds of process, destroying the normal physiological function of the cell [31]. The study of Chun-Nam Lok et al. showed that nano-silver seemed to have a membrane targeting effect and might target the bacterial membrane, leading to proton power dissipation, causing a large amount of loss of potassium ions in the cell, thereby blocking the oxidative phosphorylation process of bacteria and leading to cell death [32]. According to Siddhartha Shrivastava et al., the main mechanism by which AgNPs exhibits antimicrobial performance is to regulate cellular signaling by dephosphorylating the assumed key peptide substrates on tyrosine residues, thereby leading to signal transduction inhibition to inhibit bacterial growth, and the antimicrobial effects of NPs are not related to bacterial resistance to antibiotics [33]. Jun Sung Kim et al. believe that the mechanism of the bactericidal activity of metal NPs is due to the free radical produced on the surface of NPs, which then destroys the cell membrane and eventually leads to cell death [34] (Figure 2).

Many different types of metallic and metal oxide NPs work against bacteria, viruses and other eukaryotic microorganisms, of which AgNPs have been shown to be the most effective [35]. Metallic silver or related silver compounds have been used since ancient times to treat burns and several bacterial infections. With the emergence of antibiotics such as penicillin, the use of silver in the field of antibacterial gradually declined. However, the use of metallic silver and silver compounds as fungicides has again attracted extensive attention due to the widespread problem of drug resistance [21]. AgNPs combined with different types of antibiotics, such as penicillin, erythromycin and vancomycin, can enhance the bactericidal effect on gram-positive bacteria and gram-negative bacteria [36]. Four different formulations of silver–carbon complexes (SCCs), including micelles and NPs, are effective in the range of 0.0005–0.09 kg/m³ against medically established MDR bacteria such as MDR Acinetobacter baumannii (-), methicillin-resistant Staphylococcus aureus and klebsiella pneumoniae (-) [37]. In addition, the current applications of silver NPS mainly include external medical antibacterial dressings, implantable medical material coatings and so on [38]. Dressings [39], creams and gels made from silver NPs can effectively reduce bacterial infections in chronic wounds [40]. Silver NPs wound dressings containing poly vinyl nano-fibers also have high antibacterial properties [41]. NPs coatings play an important role in implanted medical devices and materials besides being used as antibacterial materials for external use. It is inevitable that exogenous medical materials will be used in implant surgery. The most common problems in this type of surgery are body rejection and bacterial infection. With their excellent antibacterial effect, NPs can be coated on the surface of exogenous medical materials through technical means to achieve a lasting anti-infection effect. Some researchers used the plasma immersion ion injection method to synthesize zero valent iron NPs (FeNPs) and iron oxide NPs on the surface and subsurface of titanium oxide coatings (TOCs); the synthetic Fe-NPs/TOC system has excellent cell compatibility, and the system under the condition of the dark effect on staphylococcus aureus has the specificity, and is considered to be an excellent implants coating material [42]. Similarly, AgNPs were modified on tantalum oxide coating by plasma immersion ion implantation. The results showed that the coating destroyed Staphylococcus epidermidis cell integrity in the dark, thus producing a bactericidal effect [43].

Nonetheless, when silver compounds are administered in vivo, they may have toxic effects due to prolonged exposure to soluble silver compounds. In addition to causing argyria, they can cause permanent blue-gray discoloration of the skin or eyes, liver and kidney damage, eye, skin, respiratory and intestinal irritation and changes in blood cells [44]. Studies have shown that AgNPs have significantly reduced or no toxic side effects on humans compared to metallic silver or silver compounds. However, some studies have pointed out that the particle size of AgNPs may lead to the accumulation of Ag⁺ in vivo and the environment, resulting in certain toxic and side effects [45]. It is suggested that adding appropriate coating on the surface of AgNPs can avoid aggregation in high salt medium and improve the stability of NPS. Researchers have succeeded in preparation of glutathione (GSH) coated silver NPs, confirmed that GSH capped AgNPs (GSH Ag NPs) are more antibacterially active against Gram-negative bacteria than Gram-positive bacteria, and speculated that this is due to the increased water-solubility of NPs by the GSH coating, which allows Ag to penetrate more easily into the cytoplasm, subsequently releasing silver and interacting with the local components of the cell to produce bactericidal action [46]. It has been proven that immobilizing AgNPs on the plasma coating of hexamethyldisiloxane by liquid flame spray technology can limit the escape of Ag⁺ to the environment on the premise of ensuring the antibacterial effect [47]. Overall, although NPs have a wide range of applications, they also have the potential to cause adverse effects at the cellular, subcellular and protein levels. While some NPs may appear nontoxic, they may cause disruption to cellular signal transduction and other normal cellular functions [48]. The AgNPs as antibacterial drug in the body also need further research, and some knowledge of the acute toxicity of metal NPs in vivo, such as metabolic processing, clearance, bioaccumulation and long-term effects, remains to be elucidated [49].

3.2. Antibiotic Nanocarrier

Using nanotechnology to load antibacterial drugs can not only improve the antibacterial effect of drugs, but also reduce the side effects of drugs [50]. The main pharmacokinetic characteristics of nanocarrier-encapsulated antibiotics include increased solubility [51], controlled and relatively uniform distribution in target tissues targeted delivery, sustained and controlled release, and enhanced cell internalization [52]. Nanocarriers can encapsulate hydrophilic or lipophilic drugs, increase the solubility of drugs, and promote the absorption of antibiotics in the human body. Specific drug delivery can be carried out through appropriate nanocarriers, and antibiotics can be transported to the target through nanocarriers, so as to reduce the toxic and side effects in the medication process, improve the efficacy [53]. By controlling the surface aperture of the nanocarrier, the drug release rate and amount can be controlled. Common antimicrobial drug delivery vehicles include liposomes, solid lipid NPs (SLN), polymer NPs, etc. (Figure 3) [14]. Among them, liposomes are the most widely used [54].

3.2.1. Liposomes

Liposomes are nanoscale to micron vesicles formed by encapsulating drugs in a phospholipid bilayer, which is similar to a membrane structure and is easy to fuse with infectious microorganisms [55]. Moreover, both hydrophilic and hydrophobic antibiotics can be encapsulated and retained in an aqueous core and phospholipid bilayer without chemical modification [56]. The surface of the liposomes is usually linked to polyethylene glycol, which is a hydrophilic and pliable polymer that forms a hydration film on the surface of the liposomes. It inhibits the adsorption of plasma components to the liposome surface, thereby reducing the uptake of liposomes by the reticuloendothelial system. The time of the liposome in systemic circulation is prolonged, which indirectly increases the time of drug action in vivo and improves the efficacy. There are many researches about liposomes encapsulating antibiotics as carriers. Studies have shown that liposomes encapsulation enhanced the stability of ampicillin. Free ampicillin lost 50% of its initial activity in an aqueous solution stored at four degrees Celsius for five weeks, while liposomes encapsulation of ampicillin (released from unencapsulated drugs) lost only 17% of its initial activity under the same conditions. Ampicillin, which is wrapped in liposomes, is active in bacterial colonies, independent of other cells [57]. Ciprofloxacin is an effective treatment for systemic salmonella infection. Liposome-incorporated ciprofloxacin (LIC) is more effective than free ciprofloxacin. A single injection of Liposome-incorporated ciprofloxacin was ten times more effective in preventing mortality than a single injection of free drugs [58]. Liposomes encapsulation can significantly enhance the uptake of vancomycin and teicolanin by macrophages. Vancomycin and teicolanin by entrapment in liposomes leads to increased availability of antibiotics, effectively eliminating intracellular methicillin-resistant staphylococcus aureus (MRSA) infection [59]. Liposome encapsulating streptomycin was more effective than free streptomycin in the treatment of experimental abamia complex infection in beige mice [60]. Direct injection of liposome polymyxin B into the lung can enhance the retention of pulmonary antibiotics and is an effective method for the treatment of Pseudomonas aeruginosa pulmonary infection [61]. Amikacin, an aminoglycoside antibiotic wrapped in liposomes, has recently entered clinical trials. Liposomes encapsulating aminoglycosides may increase the therapeutic index of these drugs by increasing the concentration of aminoglycosides at the site of infection and/or by reducing the toxicity of these drugs [62]. When cationic liposomes encapsulate benzyl penicillin (penicillin G (pen-G)) on the pen-G-sensitive strain of Staphylococcus aureus immobilized in the biofilm, liposome administration is most effective compared to the free drug at lower overall drug concentration and shorter exposure time [63].

3.2.2. Solid Lipid NPs (SLN)

SLN are a new submicron drug delivery system developed in the early 1990s. Its particle size is 10–1000 nm, and it is a new generation of nanoparticle drug delivery system made by adsorption or encapsulation of drugs in lipid membrane with low toxicity, good biocompatibility and biodegradable solid natural or synthetic lipids (such as lecithin, triacylglycerin, etc.) as carriers [64]. SLN is improved on the basis of combining the advantages of solid NPs and liposomes [65]. Aerosolized solid lipid particles (SLPs) combined with rifampicin, isoniazid and pyrazinamide to act on experimental tuberin were shown to increase the mean residence time and bioavailability of the drug several times with solid lipid particles, and drug loaded solid lipid particle atomization treatment was given to infected guinea pigs every 7 days; after 7 times of treatment, pulmonary/spleen tuberculosis bacilli could not be detected, and most importantly, there is no evidence of biochemical hepatotoxicity in the administration of solid lipid particle atomization. Atomized inhalation of solid lipid particle-based antituberculosis drugs is an important means to improve the bioavailability and reduce the frequency of drug administration [66]. Tobramycin-loaded SLN has a much higher bioavailability of tobramycin (TOB) in body fluids than the equivalent dose of tobramycin used with standard commercial eye drops [67]. In vivo studies using SLN as a carrier for local delivery of econazole nitrate, a broad-spectrum antifungal with antibacterial properties, have shown that compared with marketed reference gels, SLN promotes rapid penetration of oxyconazole nitrate through the cuticle after 1 h and improves drug diffusion in deeper skin layers after 3 h [68]. Five ciprofloxacin hydrochloride-loaded NPs of albumin, gelatin, chitosan (CS) and solid lipid were prepared to control the prolonged release of antibiotics in a single dose delivery system based on nanotechnology, which demonstrated that chitosan NPs and SLNs can be used as promising vectors for sustained release of ciprofloxacin to treat infections [69].

3.2.3. Polymer NPs

Biocompatible and biodegradable polymer NPs are used to control drug release. Two main types of polymer NPs are used in antimicrobial delivery: linear polymers and amphiphilic block copolymers. Most polymer NPs prepared from linear polymers are typically nanocapsules or solid nanospheres [53]. The use of biodegradable polymer NPs loaded antibacterial drugs has many advantages, such as the large molecular weight of the polymer, being able to extend the drug in the lesion site residence time and enhancing the antibacterial effect. At the same time, antimicrobials can be used to control their release by diffusion or by self-degradation of the polymer. Polymer molecular surface can be connected with some functional components with targeting effect by means of chemical bonds, which has achieved the targeting effect of antibacterial drugs. In the existing literature, the morphology and structure of polymer nanoparticles commonly used as drug carriers mainly include microspheres and microcapsules. The combination of ampicillin with polyisohexylcyanoacrylate (PIHCA) NPs greatly improved the efficacy of ampicillin in the treatment of salmonella typhimurium infection in C57BL/6 mice [70]. The experiments of emulsifying NPs formed by covalent binding of penicillin antibiotics on polyacrylate proved that the NPs had the same in vitro antibacterial properties against methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and had infinite stability toward β-lactamase [71]. N-thiolated β-lactam antibiotic was covalently bound to polyacrylate polymer matrix to produce nanoemulsion, which had strong in vitro antibacterial properties against methicillin-resistant staphylococcus aureus and better biological activity than non-polymerized antibiotics [72]. This method allows the water-insoluble drug to be directly incorporated into the nanoparticle framework, and more importantly, it does not require post-synthetic modifications in the process. The combination of amphotericin B (AmB) and poly (1-caprolactone) nanospheres increased the activity of the free drug against leishmaniasis [73]. Studies have shown that the use of NPs as drug carriers may significantly increase the activity of antibiotics in phagocytes, and that NPs may be used in the treatment of intracellular infections [74].

However, in practical application, liposomes have problems such as short shelf life and poor stability. Liposomes stored in solution may delamination or even mildew at room temperature. In addition, liposomes have a relatively low encapsulation rate for antimicrobial agents. It is easily removed by the reticuloendothelial system and can interact with cells in the physiological environment [75]. Compared with liposomes, SLN is the solid state of its granular matrix, so it has the ability to protect chemically unstable components from chemical decomposition and the possibility of regulating drug release, and is also considered as the next generation delivery system after liposomes. However, due to the small particle size, complex system and dynamic phenomenon of SLN, the characterization of SLN is a severe challenge [65]. For polymer NPs, there may be a certain toxic effect, mainly because polymer NPs will stimulate the internalization effect of macrophages, and the internalized NPs will be degraded in the cell, resulting in cytotoxicity. In addition, there are still some problems in the large-scale production of polymer NPs [76]. In practical application, different NPs have some problems. It may be a new way to solve the above problems by combining the two different carriers, giving full play to their advantages and complementing their deficiencies. Excitingly, lipid–polymer hybrid NPs have been prepared and demonstrated to enhance cell delivery in vivo, and a simpler and better mass-production method has been developed that can be industrialized based on experimental conditions [77].

4. Conclusions

The emergence of antibiotics has greatly reduced the mortality of infectious diseases, but the accompanying proliferation of drug-resistant bacteria has put public health at risk. The direct causes of drug resistance are due to the misuse of antibiotics, the lack of proper management measures and the awareness of drug use. The fundamental reason is the change in the physiological nature of bacteria. Of course, there are many mechanisms for bacteria to develop drug resistance. Researchers should follow different paths and take the mechanism of drug resistance as a reference to actively find new strategies and new drugs to fight against drug-resistant bacteria after fully understanding the mechanism of drug resistance. The advent of nanotechnology has indeed shed light on the epidemic of drug-resistant bacteria. It is difficult for bacteria to develop resistance to metal and metal oxide NPs due to their multiple antimicrobial mechanisms. Because the metal in the human body can produce toxicity, though, metal and metal oxide NPs in modern medical practice are widely used as a topical antibacterial dressing or implantation surgery material surface coating; in addition, small doses of metal and metal oxide NPs used together with the existing antibiotics, on the one hand, ensure that small doses of metal and metal oxide do not produce toxic effects to the human body, and on the other hand, can enhance the antibacterial function and alleviate MDR. What is more promising is that antibacterial drugs can be wrapped by a nanocarrier, and even different chemical groups or specific substances can be connected on the surface of the carrier as coatings for different bacterial species, so as to achieve a specific targeting effect. In this way, the efficacy can be improved while the side effects caused by antibacterial drugs can be greatly reduced. It also increases the stability of the antimicrobial and prevents it from breaking down before reaching the target site. Due to the small size effect of NPs, they can enter and deposit into bacterial hiding places that are inaccessible to ordinary drug particles, providing a new approach to combatting MDR.

However, they also have disadvantages. The pharmacokinetic characteristics of NPs in vivo are not fully understood, especially the distribution and metabolism of NPs in vivo, as well as how they are excreted from the body after the corresponding drug effect is exerted, which requires further study. For the possible toxicity of NPs, researchers should focus on how the metal and metal oxide NPs are in relation to absorption, distribution, metabolism and excretion, determine the rest of the toxic effects of particles in the metabolism of the body’s organs, to record and calculate dose, and measure its titer parameter median effective dose (ED₅₀) and the median lethal dose (LD₅₀) toxicity index. It is considered that in future research, it is a promising direction to find new and effective targets for bacteria and to use nanocarriers loaded with functional groups to attack them specifically. It is an idea to use nanotechnology to change the dosage form and mode of action of existing antibacterial substances to alleviate MDR. The authors believe that in addition to the existing antibiotics, the antibacterial substances in natural plants are also worth exploring and studying. At present, bacteria have not produced widespread resistance to the antimicrobial substances in natural plants, and natural plants are rich in species and have a variety of active ingredients, which is of research value. Although the existing studies emphasize that the antimicrobial substances in natural compounds are far less effective than antibiotics when used alone, is it not a new idea to use nanotechnology to improve their antimicrobial activity? Nanotechnology is used to change the solubility of natural antibacterial ingredients and improve their bioavailability to improve their effect.

However, the medicinal ingredients of natural plants are relatively complex and their toxic and side effects are unknown. Therefore, future research should focus on the pharmacokinetic analysis of the extracted active ingredients to understand the active dose and the exact toxic and side effects. While scientists are trying to find a new way to combat MDR, in order to prevent the further growth of drug-resistant bacteria, the government should strengthen the management of antibiotics, require all drug use units to do a good job of registration and statistics, the use of antibiotics should be strictly in accordance with the principle of not using more antibiotics and not abusing them on the premise of not threatening life and health. At the same time, the public should have the correct awareness of drug use, strictly follow the doctor’s advice and not arbitrarily change the dosage of drug use.