Charge-Competition AIEgens Induce Mitochondrial Dysfunction for Selective Eradication of Candida albicans while Restoring Vaginal Microbiota.

The principal therapeutic challenge in vulvovaginal candidiasis (VVC) is that the non-selective nature of conventional antifungal drugs, which frequently perturb vaginal microecological homeostasis and disrupt Lactobacillus barrier, lead to the emergence of recurrent infection and drug resistance. This study aims to develop novel antifungal agents capable of efficiently and selectively eradicating pathogenic fungi while protecting and promoting the growth of Lactobacilli, with real-time monitoring capabilities and significant potential for clinical application. Harnessing the principle of charge-competition, we engineered a cationic amphiphilic aggregation-induced emission luminogens (AIEgens, named as TPE-ET), where hydrophobic chain length served as a key determinant governing membrane affinity, aggregation propensity, and antimicrobial selectivity. This design empowered potent eradication of Candida albicans (C. albicans) while concomitantly favoring the proliferation of beneficial Lactobacilli. Moreover, TPE-ET disrupted C. albicans biofilms and suppressed virulence genes related to adhesion, invasion, and drug resistance. In a murine VVC model, TPE-ET reduced fungal burden by over 90%, facilitating the repair of damaged vaginal epithelium and the reconstitution of a Lactobacillus-dominat vaginal microbiome. Remarkably, TPE-ET outperformed clotrimazole in restoring healthy microecological balance, as manifested by diminished Proteobacteria abundance alongside increased Firmicutes (notably Lactobacillus) and Bacteroidetes. Mechanistic studies revealed that TPE-ET exerted its remarkable antifungal activity by targeting the mitochondrial inner membrane, disrupting the metabolism-inflammation axis and eliciting mitochondrial dysfunction. Collectively, this dual merits of membrane charge-selective targeting and AIEgens-mediated visualization established an innovative therapeutic strategy for VVC, featuring superior efficacy, exquisite selectivity, and real-time monitoring capability with significant clinical potential.