Pullulan nanoparticles inhibit the pathogenicity of Candida albicans by regulating hypha-related gene expression.

Candida albicans is a prevalent opportunistic pathogenic fungus that resides in the skin and gastrointestinal (GI) tract of humans. Under specific conditions, C. albicans cells transition from a commensal to a pathogenic state, leading to both superficial and invasive infections. Although systemic candidiasis poses a life-threatening risk, a limited number of antifungal drugs are employed for its treatment. Moreover, the emergence of resistant strains to antifungal agents underscores the pressing need for new treatment options. In this study, we propose the use of polysaccharide nanoparticles as a strategy for treating candidiasis. We synthesized phthalic pullulan nanoparticles (PPNPs) and examined their ability to inhibit the pathogenicity of C. albicans. We observed that PPNPs inhibit hyphal growth, adhesion to abiotic surfaces, and biofilm formation of C. albicans in a dose-dependent manner. This inhibitory effect is mediated by transcriptional modulation, particularly the downregulation of hypha-related genes and the upregulation of stress-responsive genes, involving the Ras/cAMP/PKA signaling pathway. Furthermore, we observed that PPNPs inhibit the adhesion of C. albicans to human epithelial cells without inducing toxicity in human cells. In addition, PPNPs inhibited the in vivo pathogenicity of C. albicans in Caenorhabditis elegans, suggesting an antagonistic effect on candidiasis. Our findings suggest that PPNPs exhibit inhibitory effects on C. albicans biofilm formation and in vivo pathogenicity, indicating their potential as a novel therapeutic agent for candidiasis.

Importance: The pathogenic process of Candida albicans, the primary causative species of candidiasis, involves hyphal growth, biofilm formation, and secretion of virulence factors. Of these factors, the biofilm, created by the secretion of extracellular matrix from adherent cells, shields cells from external threats, enabling them to withstand high concentrations of antifungal agents. Therefore, suppressing biofilm formation is a crucial aspect of combating candidiasis. This study developed phthalic pullulan nanoparticles (PPNPs) as a novel material for inhibiting C. albicans' pathogenicity. PPNPs were internalized within Candida cells and reduced pathogenicity at the gene expression level, resulting in reduced in vitro biofilm formation, adhesion to human cells, and mortality of infected Caenorhabditis elegans. Moreover, PPNPs exhibited these effects without toxicity to human cells and host animals. These findings not only indicate that PPNPs can be employed to hinder in vitro biofilm formation but also suggest their potential as a novel treatment for candidiasis.