Novel Voriconazole-Loaded Hyalurosomes Optimized for Enhanced Skin Penetration and Antifungal Activity against Candida albicans

Cutaneous candidiasis, mainly caused by Candida albicans , is a growing global health concern and is listed by WHO as a high-priority fungal threat. Suboptimal penetration of conventional vehicles limits the efficacy of current topical antifungals, increasing the risk of severe and invasive infections. Therefore, there is an innovative research field in advanced topical delivery systems to improve drug deposition, retention and antifungal efficacy. The main objective of this work was to develop nanocarriers based on hyalurosomes for the delivery of voriconazole (VCZ) and evaluate their potential to enhance the drug’s cutaneous penetration and antifungal activity. Four VCZ-loaded hyalurosomal formulations were prepared (H1-H4) by modulating the proportions of phospholipid and polyols. Although changes in some physicochemical properties were observed, all the VCZ-loaded nanosystems were nanosized (< 140 nm), spherical, multilamellar and exhibited high entrapments efficiencies (> 72 %), excellent biocompatibility with human keratinocytes and potent antifungal activity against C. albicans . VCZ release from formulation H1 (1 % phospholipid, 10 % ethanol) followed a Fickian mechanism, while H2–H4 (4-10 % phospholipid, 2.5-10 % ethanol) exhibited anomalous diffusion involving both diffusion and matrix relaxation or erosion. Additionally, H1 and H2 (1-4 % of phospholipid, 10 % ethanol) achieved significantly enhanced drug penetration into deeper skin layers and superior in vivo antifungal efficacy compared to VCZ dispersion. The results highlight the potential of hyalurosomes as a next-generation topical antifungal delivery system, effective against both superficial and invasive candidiasis, with formulations H1 and H2 emerging as the most promising candidates for the treatment of the more invasive forms.