Aptamer-mediated targeting of candidalysin attenuates oral candidiasis-associated inflammation in a murine model

Background Oral candidiasis involves fungal invasion and virulence-mediated mucosal injury. Candidalysin, a hypha-associated peptide toxin secreted by Candida albicans, damages epithelial barriers and elicits inflammation.Objective To identify candidalysin-binding DNA aptamers that attenuate epithelial injury and inflammation and evaluate their potential as locally delivered anti-virulence agents.Design: A previously generated pool of 80 aptamers was re-evaluated using surface plasmon resonance, molecular docking, and functional assays. Protective effects were examined in human oral epithelial TR146 cells using synthetic candidalysin, ECE1-deficient and reconstituted strains, and background-matched controls. Topical PEGylated aptamers were evaluated in male mice using a permissive oral candidiasis model combining corticosteroid immunosuppression, mucosal abrasion, and a high inoculum.Results Apt09, Apt48, and Apt60 exhibited nanomolar binding, with Apt60 showing the most favourable overall profile and a dissociation constant of 71 ± 14 nM. Apt60 reduced candidalysin-induced lactate dehydrogenase release into cell-culture supernatants and lowered IL-1β and IL-6 secretion. Strain comparisons supported an ECE1-dependent protective effect consistent with candidalysin neutralisation. Apt60 did not detectably alter fungal growth, viability, or hyphal formation in vitro. In mice, topical PEGylated aptamers reduced lesion scores, preserved tissue architecture, and lowered tissue cytokine levels and caspase-1 activity, with Apt60 showing the strongest overall response among the tested aptamers. No statistically detectable reduction in oral fungal burden was observed under the conditions tested.Conclusions Apt60 is a promising candidalysin-targeting anti-virulence candidate. These findings support further evaluation of local toxin neutralisation for Candida-associated mucosal disease, while efficacy beyond the permissive male-mouse model remains to be established.