Advanced Vaginal Nanodelivery of Losartan Potassium via PEGylated Zein Nanoparticles for Methicillin-Resistant Staphylococcus aureus

<b>Background/Objectives:</b> PEGylated zein nanoparticles (PZNs) loaded with losartan potassium (LOS) were developed as a repurposed treatment for vaginal methicillin-resistant <i>Staphylococcus aureus</i> (<i>MRSA)</i> infection. PZNs were prepared using the ethanol injection method with different types and amounts of Brij^® surfactant. <b>Methods:</b> The prepared formulations were optimized using a D-optimal mixture design via Design-Expert^® software version 13. The assessed responses included entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). <b>Results:</b> The optimized PZNs, composed of 30 mg Brij^® O20 and 10 mg zein, exhibited spherical particles with an EE% of 90.58 ± 1.20%, PS of 200.81 ± 1.39 nm, PDI of 0.395 ± 0.01, and ZP of -36.59 ± 0.05 mV. Confocal laser scanning microscopy confirmed complete deposition of fluorescein-labeled PZNs within vaginal tissues. Ex vivo studies showed that PZNs resulted in prolonged permeation of LOS compared to the LOS solution. In a murine model of MRSA infection, the optimized PZNs demonstrated superior therapeutic efficacy over the LOS solution. Histopathological examinations confirmed the safety of the tested formulations. <b>Conclusions:</b> In conclusion, the optimized PZNs present a promising approach for the treatment of MRSA-related vaginal infections.