## 3 Controlled Antibiotic Delivery
### Endogenous Stimuli-Responsive Antibiotic Delivery
Likewise, the high expression level of microbial **enzymes** in the infectious site is another powerful trigger for antibiotic release. Most bacteria secrete specific enzymes into the environment to digest macromolecules as nutrients for growth and maintenance. In some cases, bacteria produce specific extracellular enzymes as a defense mechanism to break down toxic compounds in their surrounding environment, including antibiotics. By taking advantage of this property, many enzymes and their respective stimuli-responsive nanosystems for antibiotic delivery have been developed, as shown in Table 2. Broadly, the technical point of this design is based on the insertion of sensitive polymers or enzyme-cleavable chemical bonds into the nanocarir matrix. For example, Lipase is one of the most widely targeted enzymes in enzyme-responsive systems due to its particularly abundant presence at infection sites. By designing NPs based on polyphosphoester or phosphoester bonds, which can be readily degraded by bacterial lipases, many reported drug delivery nanosystems allowed for a precise release of antibiotics at the site of inflammation, eliminating undesirable side effects caused by premature antibiotic leakage [54; 55; 56; 57; 58; 59]. In another example, [PERSON] et al. developed an \"on-site transformation\" strategy to precisely deliver antibacterial agents in the presence of gelatinase secreted by bacteria (Figure 5A) [60]. The design is based on transformable polymer-peptide conjugates consisting of three elements, a chitosan backbone, an enzyme-cleavable peptide with a polyethylene glycol (PEG) terminal, and an antibacterial peptide. The conjugates were self-assembled into NPs and morphologically transformed into nanofibers in the presence of gelatinase, leading to the high exposure of antimicrobial peptide residues with bacterial membranes. Taking advantage of the in situ morphological transformation, this strategy offered various merits in terms of increasing binding, effective accumulation, prolonged retention at the bacterial infection environment, and enhanced antibacterial activity. In the same design, the development of nanocarriers responsive to antibiotic-resistant enzymes is another innovative application in which the killing activity is only activated within antibiotic-resistant bacterial infections and by their enzymes. [PERSON] et al. reported self-assembled polymeric vesicles from amphiphilic diblock copolymers that were susceptible to degradation by penicillin G amidase (PGA) and \(\beta\)-lactamase (Bla) (Figure 5B) [61]. During NPs' formation, different antimicrobial agents (with hydrophilic or lipophilic properties) could be loaded into either hydrophobic bilayers or aqueous interiors. These formulations showed selective antibiotic delivery to MRSA strain in vitro and enhanced wound healing in a murine model. Similarly, considerable research has also focused on constructing systems in response to **reduced glutathione** in intracellular pathogen sites, **nitric oxide, or **reactive oxygen  
Figure 5: Examples of enzyme-responsive nanocarriers for antibiotic delivery. (**A**) Illustration of the self-assembly of polymer–peptide conjugate NPs and the principle of enzyme-induced morphology transformation with the high antibacterial ability (reprinted with permission from [60], copyright 2017 John Wiley and Sons). (**B**) Illustration of enzyme-responsive polymeric vesicles for bacterial strain-selective delivery of antibiotics. Polymeric vesicles are self-assembled from synthesized polymers subjected to side-chain cleavage and microstructural transformation in response to penicillin G amidase and \(\beta\)-lactamase. This process is accompanied by sustained release and bioactivity recovery of encapsulated antibiotics (reprinted with permission from [61], copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). species** (ROS) in inflammatory environments. These studies have highlighted the potential of antibiotic delivery triggered by endogenous factors (Table 2).