Targeting multidrug-resistant Candida: CuxTe nanoflowers synergistically facilitate fungal clearance via cuproptosis death and host immune activation

Abstract 1 Candida species are common infectious pathogens that can cause invasive infections with potentially life-threatening consequences. Current treatments for invasive Candida infections are primarily azoles and echinocandins. However, emerging antifungal drug resistance compromises therapeutic efficacy. Herein, a stable Cu x Te nanoflower was designed to combat fungal infections via cuproptosis death and immune activation. Firstly, Cu and Te precursors were added to an auxiliary reducing agent and solvent, and Cu x Te nanoflowers with a multibranched dendritic structure were synthesized via a temperature-controlled solution-phase method. Cu x Te nanoflowers effectively inhibit fungal growth, damage fungal cell membranes and walls, and show significant fungicidal activity even against the multidrug-resistant fungus Candida auris . Furthermore, they significantly disrupt fungal biofilms and inhibit their growth and maturation. Cu 2+ ions released in the weakly acidic fungal microenvironment penetrate fungal cells, inducing copper overload. Transcriptional and cytological analyses revealed that Cu x Te treatment disrupted the mitochondrial membrane potential, altered membrane permeability, triggered insoluble Dlat protein aggregation, blocked the TCA cycle, impaired mitochondrial function, and ultimately induced fungal cuproptosis death. Simultaneously, they promote proinflammatory macrophage polarization, exerting synergistic antifungal effects. In summary, this therapeutic strategy integrates synergistic dual-pathway mechanisms: fungal cuproptosis death and immune activation, providing a new approach for treating antifungal infections. • Multi-branched Cu x Te nanoflowers were synthesized via wet chemistry, showing exceptional metalloenzyme-like activity. • They synergistically disrupt fungal structures including biofilms and inhibit growth in vitro. • They induce both fungal cuproptosis-like and host immune activation for better clearance. • They accelerate healing of fungal-infected wounds in mice with high biocompatibility.