## 4 Targeted Delivery of Antibiotics to Sites of Infection
### Active Targeting
#### 4.2.2 Active Targeting to Infectious Microenvironments  
The infectious microenvironments are characterized by the overexpression of several factors such as bacterial toxins, inflammatory mediators, and recruited immune cells for bacterial clearance. Similar to the idea of endogenous drug delivery systems, many interesting targeting ligands of infectious microenvironments have been designed for coating nanocarriers. For example, inflammatory activation of the endothelium triggers the production or upregulation of several molecules, promoting leukocyte recruitment. Among them, intercellular adhesion molecules (CAMs) play a significant role in leukocyte adhesion and infiltration from the peripheral blood into the inflamed tissues. As a result, various targeting ligands of CAMs have been exploited for selective delivery of active agents to specific inflamed tissues (e.g., neutrophil-membrane, \(\gamma\)3 peptide, anti-ICAM-1 antibody) (Table 3) [111; 112; 113]. As an example, by coating anti-CAM antibodies on bioesponsive NPs, [PERSON] et al. developed a nanocarrier system able to co-deliver antibiotic and anti-inflammatory drugs to target infectious microenvironments (Figure 10A) [55]. This strategy has simultaneously enabled bacteria elimination and alleviated host inflammatory response in both acute lung bacterial infection and the sepsis mouse model. In the case of intracellular bacterial infections, instead of targeting the bacteria, nanosystems were developed to target infected host cells through various types of specific receptors present on their surfaces. Additionally, the ideal ligands could promote intracellular delivery of NPs, then effectively deliver antibiotics to subcellular compartments containing bacteria. Various ligands have been exploited to functionalize the nanocarrier's surface for targeting infected host cells, such as mannose [57; 121], dextran [103], folic acid [119], lectins [41], peptides [122; 123], and bacterial membrane or its derivatives (mimicking bacterial phagocytosis) [116; 117; 118] (Table 3). For example, immune cells including Kupffer cells, alveolar, peritoneal, splenic macrophages, dendritic cells, and a subset of vascular endothelial cells have been shown to express high levels of mannose receptors [124]. Therefore, mannosylated NPs have been used to deliver antibiotics more specifically to infected macrophages, as well as to infection sites through macrophage transport (macrophage hitchiking). In this respect, [PERSON] et al. showed that the targeting efficiency of a mannosylated nanogel to macrophages was significantly higher than that of an unmodified nanogel in a zebrafish embryo model (Figure 10B) [57]. In addition, upon entering macrophages, the polyphos-phoester crosslinked core of NPs was degraded by the phosphatase and phospholipase (secreted by MRSA during macrophage infection), resulting in the fast release of the antibiotic payload and the superior inhibition of intracellular bacterial growth. In an innovative idea, [PERSON] et al. proposed a strategy, namely, \"Kill the Real with the Fake\", using the membrane of extracellular vesicle (EV) secreted by bacteria as an active-targeting ligand for an antibiotic carrier (Figure 10C) [116]. Macrophages, after exposure to the bacterium, showed enhanced expression of various recognition receptors, allowing the greater innate immune response upon reinfection with the same type of pathogen. As a result, EV membrane coating of PLGA NPs endowed the particle with an active targeting capacity both in vitro and in vivo. Intravenous administration of antibiotic-loaded NPs coated with the EV membrane proved to be more efficient than free antibiotics and bare NPs in the kidney and lung, which bear the highest metastatic bacterial burden. The extended application of bacterial EVs has also been explored in several other studies, in which nanocarriers based on EVs (e.g., _A. baumannii, E. coli_) could protect antibiotics and increase their bacterial uptake [125; 126].