**4. Targeted therapy of infections using nanoparticles**

The hydrophilic nature of some antibiotics prevents thier capacity to penetrate the cells and, furthermore, the internalized molecules are mostly accumulated in lysosomes, where the bioactivity of the drug is low. Therefore, limited intracellular activity against sensitive bacteria is often found [13, 14]. Thus, the use of drug delivery systems (DDS) has been suggested for passive targeting of infected cells of the mononuclear phagocytic system to enhance the therapeutic index of antimicrobials in the intracellular environment, while minimizing the side effects associated with the systemic administration of the antibiotic [15]. The pathophysiolog‐ ical and anatomical changes of the affected tissues in a disease state offer many possibilities for the delivery of various nanotechnology-based products [16]. Bacteria gains antibiotic resistance due to three reasons namely: 1) modification of active site of the target resulting in reduction in the efficiency of binding of the drug, 2) direct destruction or modification of the antibiotic by enzymes produced by the organism or, 3) efflux of antibiotic from the cell [17]. Nanoparticles (NPs) can target antimicrobial agents to the site of infection, so that higher doses of drug can be given at the infected site, thereby overcoming existing resistance mechanisms with fewer harmful effects upon the patient [18]. As with nanoparticles targeting intracellular bacteria, nanoparticles targeting the site of infection can release high concentrations of antimicrobial drugs at the site of infection, while keeping the total dose of drug administered low. Nanoparticles can be targeted to sites of infection passively or actively. Passively targeted nanoparticles selectively undergo extravasation at sites of infection, where inflammation has led to enhanced blood vessel porousness. Actively targeted nanoparticles contain ligands (e.g. antibodies) that bind receptors (e.g. antigens) at sites of infection [19]. Passive targeting with nanoparticles, however, faces multiple barriers on the way to their target; these include mucosal barriers, nonspecific uptake of the particle and non-specific delivery of the drug (as a result of uncontrolled release) [20]. Passive nanoparticulate targeting of chemotherapeutics to the cells and organs of the reticuloendothelial system (RES) has been a significant area of research for the treatment of chronic infectious diseases. The RES comprises monocyte-lineage immune cells such as macrophages and dendritic cells, as well as the spleen, liver, and kidneys. These components of the RES are consistently implicated as sites of nanoparticle clearance and localization [21]. The few studies that have compared targeted and nontargeted systems have demonstrated that the role of targeting ligands in localization at the target site is application dependent. Targeted delivery to atherosclerotic lesions is greatly enhanced by targeting ligands which impart an improved ability to accumulate at the target site [22]. Many active targeting strategies use the enhanced permeability and retention (EPR) effect, so that active and passive targeting mechanisms act synergistically that lead to higher concentration of nanostructures in the infected region than that in healthy tissues [23]. Targeted antimicrobial drug delivery to the site of infection, particularly intracellular infections, using NPs is a sensational prevision in treating infectious diseases [24, 25]. Intracellular microorganisms are taken up by alveolar macrophages (AMs), intracellulary survive or reproduce, and are persistent to the antimicrobial agents. Antibiotics loaded NPs can enter host cells through endocytosis, followed by releasing the payloads to delete intracellular microbes [26, 27]. The need to target drugs to specific sites is increasing day by day as a result of therapeutic and economic factors. Nanoparticulate systems have shown enormous potential in targeted drug delivery, specially to the brain [28].

**5.1. Advantages of nanoantibiotics**

The use of NPs as delivery vehicles for antimicrobial agents suggests a new and promising model in the design of effective therapeutics against many pathogenic bacteria [35]. Antimi‐ crobial NPs propose several clinical advantages. First, the surface properties of nanoparticles can be changed for targeted drug delivery for *e.g.* small molecules, proteins, peptides, and nucleic acids loaded nanoparticles are not known by immune system and efficiently targeted to special tissue types [36]. Second, nanocarriers may overcome solubility or stability issues of the drug and minimize drug-induced side effects [37]. Third, using nanotechnology, it may be possible to achieve co-delivery of two or more drugs or therapeutic modality for combination therapy [33]. Fourth, NP-based antimicrobial drug delivery is promising in overcoming resistance to common antibiotics developed by many pathogenic bacteria [38]. Five, adminis‐ tration of antimicrobial agents using NPs can progress therapeutic index, extend drug circulation (i.e., extended half-life), and achieve controlled drug release, increasing the overall pharmacokinetics [30]. Six, the system can be used for several routes of administration including oral, nasal, parenteral, intra-ocular etc [39]. Thus, antimicrobial NPs are of great

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interest as they provide a number of benefits over free antimicrobial agents [35].

Although nanoantibiotics promises significant benefits and advances in addressing the key obstacles in treating infectious diseases, there are foreseeable challenges in translating this exciting technology for clinical application [40]. Profound knowledge about the potential toxicity of nanoantibiotics is also needed to guarantee successful clinical translation [41]. The toxic effects of antimicrobial NPs on central nervous system (CNS) are still unknown, and the interactions of NPs with the cells and tissues in CNS are poorly understood [42]. Furthermore, NPs represent size-specific properties that limit the use of currently available *in vitro* experi‐ ments in a general way, and there is no standardized definition for NP dose in mass, number, surface area, and biological samples (e.g., blood, urine, and inside organs) [43, 44]. This means that there is a high request to develop new characterization techniques that are not affected by NP properties as well as biological media [45]. NPs usually have short circulation half-life due to natural defense mechanism of human body for eliminating them after opsonization by the mononuclear phagocytic system. Therefore, the particles surfaces need to be changed to be hidden to opsonization [46]. A hydrophilic polymer such as polyethylene glycol is prevalently utilize for this purpose because it has worthwhile characteristics such as low degree of immunogenicity and antigenicity, chemical inertness of the polymer backbone, and availabil‐

Perfectly, nanoparticulate drug delivery system should selectively accumulate in the necessary organ or tissue and at the same time, penetrate target cells to deliver the bioactive agent [48]. It has been proposed that, organ or tissue accumulation could be achieved by the passive or

**5.2. Disadvantages of nanoantibiotics including nanotoxicology**

ity of the terminal primary hydroxyl groups for derivatization [47].

**6. Nanotechnology-based drug delivery systems**
