ZIF-8-coated ZnO with pH-responsive natamycin release boosting the antifungal and anti-inflammation activity to treat fungal keratitis

Fungal keratitis (FK) is a grave infectious condition. The conventional therapeutic agent natamycin (NATA) has several disadvantages, such as low bioavailability, insufficient solubility, and restricted permeability. To identify a novel method for treating FK with pH-responsive and site-specific NATA release. In this study, ZnO@ZIF-8 (ZnO-Z), which was synthesized using a pH-responsive zeolitic imidazolate framework-8 (ZIF-8) encapsulating ZnO nanospheres, acts as the carrier to load NATA. The drug release experiment demonstrated that NATA@ZnO-Z rapidly released NATA in an acidic environment while exhibiting excellent sustained-release performance for up to 24 hours. NATA@ZnO-Z significantly inhibited <i>Aspergillus fumigatus</i> (<i>A. fumigatus</i>) growth at a concentration of 1 μg mL^-1 after 24 hours. At 5 μg mL^-1, it inhibited 90.34% of the fungal biofilm formation. Furthermore, NATA@ZnO-Z disrupted fungal cell membranes and altered oxidative stress-related indicators, including ROS, MDA, SOD, and catalase levels. Moreover, NATA@ZnO-Z not only promoted M2 macrophage polarization and suppressed the expression of inflammatory mediators (IL-1β, IL-6, and TNF-α) <i>in vitro</i> but also effectively reduced neutrophil infiltration <i>in vivo</i>. These findings highlight that NATA@ZnO-Z can serve as a novel therapeutic approach for FK with antifungal and anti-inflammatory effects and intelligent release.