Bioactive Potential of Chitosan–Oleic Acid Nanoparticles Loaded with Lemon Peel Essential Oil for Topical Treatment of Vulvovaginal Candidiasis

The rising incidence of vulvovaginal candidiasis (VVC) has been leading to the development of alternative antifungal therapies. This study aimed to develop a topical chitosan-oleic acid nanoparticle (CH-OA-NP) cream loaded with lemon peel essential oil (LPEO) for VVC treatment. The characterization of the optimal nanoparticle formulation (F4: 10 g/L CH, 2:1 OA/LPEO ratio) showed high encapsulation efficiency, stability, and controlled release. Moreover, it was characterized regarding its particle size, polydispersity index, zeta potential, and chemical/morphological profile. LPEO-related compounds (e.g., eriodictyol) were identified through LC-ESI-QqTOF-HRMS in the cream matrix, suggesting the preservation of LPEO potential bioactivities after formulation. In silico docking of 12 LPEO metabolites revealed that compounds such as citronellic acid exerted inhibitory effects against several inflammation-associated enzymes (e.g., 14-α-Demethylase). In vitro antimicrobial tests demonstrated remarkable activity against <i>Candida albicans</i>, Gram-negative (e.g., <i>Escherichia coli</i>), and Gram-positive (e.g., <i>Staphylococcus aureus</i>) bacteria. <i>In vivo</i> studies in a rat model of VVC revealed significant antifungal, anti-inflammatory, and immunomodulatory effects of the LPEO-CH-OA-NP cream (5% and 10%), leading to reduced MDA, MPO, and IL-1β levels and increased GSH activity. This novel formulation potentially offers a promising alternative therapy for VVC, addressing the current antifungal therapies' limitations, counteracting drug resistance.