## 3 Controlled Antibiotic Delivery
### Exogenous Stimuli-Responsive Antibiotic Delivery  
Although endogenous stimuli enable the efficient triggering of antibiotic release, their low sensitivity and high biological variability from one individual to another may affect the clinical efficacy of these dosage forms. Hence, external stimuli can be recruited for additional specificity and sensitivity of the antibiotic delivery systems (Table 2). In the ideal case, there will be almost zero drug release until stimuli are applied. Further, compared to endogenous stimuli, the exogenous stimuli-responsive systems are much easier to spatially and temporally control. However, minimal damage to the surrounding healthy tissues and depth penetration of the treatment stimuli are two key factors determining this dosage form's success. The **light** is among the most popular exogenous triggers for smart drug delivery systems due to its high biocompatibility, practicability, and precise control. Various light-responsive nano-systems utilizing ultraviolet (UV), visible light, and near-infrared (NIR) have been intensively applied for on-demand antibiotic release [76; 77; 78; 84]. In addition, light therapies such as photothermal and photodynamic therapy are currently used clinically as alternative treatment strategies to antibiotics [85]. Light-triggerable delivery systems can be achieved through different mechanisms, such as light-induced isomerization, bond cleavage, and disaggregation of carrier materials. The tissue penetration depth is the major obstacle of light-triggered delivery systems. While UV or visible light-trigger can only be applied to regions directly illuminated (penetration depth through the tissue less than 1 mm), such as the skin and the eye, NIR lasers offer deeper tissue penetration (1-3 mm), lower scattering properties and with minimal photodamage. For example, [PERSON] et al. recently reported an injectable hydrogel composed of glycol chitosan and ciprofloxacin-loaded polydopamine NPs (Gel-Cip) as an on-demand antibiotic delivery platform under NIR light irradiation (Figure 6A) [77]. On the one hand, polydopamine NPs could efficiently convert NIR light into heat, indicating their excellent photothermal. On the other hand, the aromatic rings on the surface of polydopamine NPs enabled the adsorption of ciprofloxacin via \(\pi\)-\(\pi\) stacking interactions, which could then be released upon NIR light irradiation. Taken together, these two effects acted in a synergistic way to eliminate bacteria more effectively and inhibited persistent _S. aureus_-induced infections in a mouse model and mouse skin defect model. Similar to light, the **ultrasound**-triggered drug delivery system is also of particular interest for local on-demand delivery of antimicrobials. One main advantage of ultrasound is that it allows depositing high levels of energy on a small region of diseased tissue without harming the surrounding tissue [86]. Concurrently, ultrasound is well known as a potential combination therapy with antibiotics to increase antimicrobial efficacy (e.g., synergistic effects, biofilm degradation) [87]. \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & & **Stimulus** & **Nanocarrier** & **Stimuli-Responsive Compound** & **Ref.** \\ \hline \multirow{8}{*}{**Stimuli-Responsive Computation**} & \multirow{2}{*}{Light: Ultraviolet (UV), visible light, and near-infrared (NIR)} & \multirow{2}{*}{Dendrimer} & Polymer–antibiotic conjugate via photodexable ortho-nitrobenzyl & [76] \\ \cline{3-5}  & & & Polymeric NPs & polydopamine, Polypyrrole & [77; 78] \\ \cline{2-5}  & \multirow{4}{*}{Ultrasound} & \multirow{2}{*}{Polymeric NPs/MPs} & Polymer matrix & \multirow{2}{*}{[79]} \\  & & & (alginate, PLGA) & \\ \cline{3-5}  & & & Hybrid NPs & Complex Vancomycin-peptide & \\ \cline{3-5}  & & & target sequence (-D-Ala-D-Ala) & [80] \\ \cline{2-5}  & \multirow{2}{*}{Magnetic field} & \multirow{2}{*}{Polymeric NPs/MPs} & \multirow{2}{*}{Iron oxide NPs} & \multirow{2}{*}{[81; 82; 83]} \\ \cline{3-5}  & & & & \\ \end{tabular}
\end{table}