Nanotechnology-driven synergy: research effects of curcumin nanosuspension and fluconazole combination in overcoming azole resistance in <i>Candida albicans</i>

The increasing incidence of invasive fungal infections-particularly disseminated candidiasis caused by <i>Candida albicans</i>-highlights the need for innovative therapeutic strategies. This study evaluates the antifungal activity of a curcumin nanosuspension (CNS), both alone and in combination with azole drugs, focusing on its potential to counteract drug resistance. CNS substantially improved the aqueous solubility and enabled sustained release of curcumin <i>in vitro</i>, overcoming its inherent pharmacokinetic limitations. Checkerboard assays identified synergistic effects between CNS and fluconazole against planktonic cells (fractional inhibitory concentration index [FICI]: 0.38-0.5) and early biofilms of <i>C. albicans</i> (FICI < 0.5). Morphological analyses revealed that the combination suppressed hyphal growth and disrupted biofilm integrity-critical virulence attributes of <i>C. albicans</i>. Further mechanistic observations suggested that the enhanced antifungal activity may involve facilitated drug uptake and suppression of efflux function, alongside reduced expression of adhesion-related genes (<i>ALS1</i>, <i>ALS3</i>, <i>HWP1</i>, and <i>EFG1</i>). These results underscore a promising nanotechnology-based approach to enhance the efficacy of conventional azoles through combination therapy.IMPORTANCEThis study provides a novel nanotechnology-based strategy to overcome azole resistance in <i>C. albicans</i>, a major clinical pathogen responsible for life-threatening systemic infections. By formulating curcumin into a stable nanosuspension (CNS), we significantly enhanced its solubility and bioavailability, overcoming a fundamental limitation that has hindered its clinical application. More importantly, we demonstrate that CNS acts synergistically with fluconazole, effectively restoring its efficacy against resistant planktonic cells and biofilms through dual mechanisms: increasing intracellular drug accumulation by inhibiting efflux pumps and suppressing key virulence traits including hyphal formation and adhesion. This combinatory approach not only reduces the required drug dosage and potential toxicity but also provides a promising therapeutic avenue against biofilm-associated refractory candidiasis. Our findings highlight the potential of harnessing natural product-nanocarrier systems to extend the lifespan of existing antifungals and combat drug-resistant fungal infections.