A "three-in-one" thermosensitive gel system that enhances mucus and biofilm penetration for the treatment of vulvovaginal candidiasis.

The special physiological barriers of women, such as vaginal mucus and self-cleaning behavior, pose great challenges for the treatment of vulvovaginal candidiasis (VVC), and the drug resistance caused by fungal biofilms limits the application of existing antifungal drugs. Based on this, we designed a "three-in-one" thermosensitive gel system (AF/BP Gel) loaded with antibiofilm nanoparticles (AF NPs) and mucus penetration-assisting nanoparticles (BP NPs) to achieve vaginal adhesion while enhancing mucus and biofilm penetration. AF NPs were loaded with farnesol (FAR) and amphotericin B (AMB), and FAR is one of quorum sensing molecules which can interfere with biofilm-related genes such as ALS3, HWP1, RAS1, CPH1, EFG1, NRG1, TUP1, UME6, and disperse mature biofilm, thus playing a synergic antibiofilm role with AMB. BP NPs was loaded with bromelain (BRO), which cleared the mucus barrier for AF NPs and help it penetrate deep into the infection. These two kinds of nanoparticles use the thermosensitive gel matrix to reach the surface of the vaginal mucosa uniformly and persistently to overcome the obstacle of vaginal self-cleaning. AF/BP Gel showed great anti-candida albicans activity in vitro and in vivo, and greatly improved the inflammatory conditions in VVC mice. Overall, this "three-in-one" thermosensitive gel system can overcome multiple physiological barriers and resist different periods of biofilm, providing a new platform for treating vagina-associated infections.