## 4 Targeted Delivery of Antibiotics to Sites of Infection
### Passive Targeting: Enhanced Permeability and Retention Effect  
The enhanced permeability and retention (EPR) effect is the property through which macromolecules can extravasate and accumulate in injured areas such as inflammation, infection, infarcts, and especially in the tumor-vascular area (angiogenic switch) [89; 90; 91]. The common feature of these lesions is frequently associated with abnormalities of the blood vasculatures, including the formation of an inter-endothelial cell gap (increasing vascular permeability) and dysfunctional lymphatic drainage (decreasing the efflux of macromolecules). In addition, bacterial components are also known to activate various inflammatory mediators that directly stimulate vascular permeability in the infection site [88]. Through this \"passive\" targeting mechanism, nanocarriers with prolonged blood circulation time have a better chance to accumulate at the infectious site, thereby enhancing antibiotic bioavailability (Figure 7). As a result, a higher antibiotic concentration to the site of interest would be obtained while reducing damage to surrounding tissues, which cannot be achieved by systemic administration of the free-form antibiotic. Although this is not a new concept, the clinical application of the EPR effect in drug nanocar delivery systems is still challenged, and there is always room for improvement. Indeed, besides the EPR effect, NPs are subjected to opsonization processes (protein corona formation) and rapid uptake by the mononuclear phagocyte system (MPS) or reticuloendothelial system (RES) in the liver and the spleen, resulting in their rapid elimination from the bloodstream. These undesirable interactions are closely related to the physicochemical properties of the nano-systems, such as particle size, shape (chemical structure), surface charge, and surface coating. Subtle changes in these parameters may significantly affect the transport behavior of nanocarriers in the human body. In this regard, the main focus of the researchers is to develop strategies that allow limiting the opsonization and sequestration by the MPS/RES, thereby prolonging the circulation time of the nanocarriers in blood vessels. It must be noted that the accumulation of NPs in macrophages makes them potentially useful for the treatment of intracellular infections [92]. As a result, these targeting systems do not necessarily possess a prolonged circulation time in blood flow to ensure the efficient uptake of infected macrophages. In contrast, in the treatment of bacterial infections located outside the MPS, passive targeting requires nanocarrier systems exhibiting a longer circulation half-life to allow a sufficient amount of antibiotic caragos to reach the target area. Several strategies have been used to protect NPs from the natural defense system of the body via manipulating the physicochemical characteristics of NPs. Among them, modifying the NPs' surface is the most frequently used method since surface properties play a crucial role in protein adsorption and interaction with host defense. For example, grafting of PEG to the surface provided a hydrating layer that hindered the formation of a protein corona [93], while the coating of NPs with host cell membranes (e.g., red blood cells) or'self' peptide (mimicking the process of recognition of host cells in vivo, e.g., CD47) provided a biomimetic surface as active stealth strategy to the host's defenses (Figure 7) [94]. However, like other drug dosage forms, any substantial adjustments in their properties may cause undesirable changes in their stability or interaction with biological systems. Therefore, to ensure maximal targeting efficiency, NPs' characteristics should be optimized for each drug delivery purpose. For example, NP-surface PEGylation with a neutral charge is widely used to reduce nonspecific interactions, leading to prolonged circulation. However, the neutral surface lacks the significant bacterial binding ability, limiting the antibiotic delivery efficacy of these systems [95]. To address this issue, [PERSON] et al.