Innovative dual-functional hybrid cationic PEGylated proniosomes as a smart nano-platform for Boosted vaginal delivery: multi-level in-vitro, ex-vivo, microbiological, and in-vivo studies

<b>Introduction:</b> Vaginal candidiasis remains a recurrent fungal infection affecting millions of women worldwide, necessitating innovative local delivery systems to overcome poor drug solubility and mucosal barriers. This study introduces Dual-Functional Hybrid Cationic PEGylated Proniosomes (DHCPP) as a smart nano-platform designed to boost the vaginal delivery of Fenticonazole Nitrate (FTN). <b>Methods:</b> DHCPP systems were fabricated via the coacervation phase separation method and optimized using a full 2³ factorial design, achieving a high desirability value of 0.931. The optimized DHCPP exhibited an encapsulation efficiency of 91.61%, particle size of 238.85 nm, and zeta potential of +58.85 mV, ensuring colloidal stability and efficient mucosal interaction. <b>Results:</b> <i>In-vitro</i> characterization using TEM and FTIR verified the formation of uniform spherical vesicles and successful FTN encapsulation without chemical incompatibility. Mucoadhesion testing revealed superior adhesive strength, indicating prolonged vaginal residence, while drug release followed a diffusion-controlled pattern. The optimized DHCPP was incorporated into a carbopol-based gel exhibiting pseudo-plastic rheology and pH compatibility with the vaginal environment. Multi-scale <i>ex vivo</i> and <i>in vivo</i> evaluations revealed a 2.36-fold permeation enhancement compared to FTN gel, consistent with deeper mucosal penetration observed via confocal microscopy. The microbiological assessment indicated a pronounced reduction in MIC and MFC values and a remarkable improvement in biofilm inhibitory effect, highlighting enhanced antifungal efficacy. Histopathological examination verified the mucosal safety of the optimized gel. <b>Conclusion:</b> The developed DHCPP represents an innovative, multifunctional, and biocompatible delivery system offering enhanced vaginal permeation, prolonged retention, and potent antifungal activity for the effective management of vaginal candidiasis.