Synergistic wall digestion and cuproptosis against fungal infections using lywallzyme-induced self-assembly of metal-phenolic nanoflowers
Fang Liu, Yongcheng Chen, Yue Huang, Yutong Li, Zhouyu Lu, Haijie Han, Xiaohui Song, Qiao Jin, Jian Ji
Abstract
Fungi are very common infectious pathogens, which may cause invasive and potentially life-threatening infections. However, the efficacy of antifungal medications remains limited. Herein, a Cu2+-phenolic nanoflower is designed to combat fungal infections by combining cuproptosis and cell wall digestion. Firstly, protocatechuic acid (PA)-Cu2+ (PC) nanopetals are prepared by coordination interaction. Lywallzyme (Lyw) is then added to induce the self-assembly of PC to form Lyw loaded PC (PCW) nanoflowers. PCW nanoflowers can effectively adhere to fungal surface and Lyw can digest fungal cell walls to facilitate Cu2+ to penetrate into fungal interior, thereby exerting a synergistic fungicidal effect. PCW nanoflowers exhibit excellent fungicidal activity even in protein-rich and high-salt conditions, where dissociative Cu2+ completely loses fungicidal activity. Transcriptome sequencing analysis reveals that PCW can lead to fungal cuproptosis. The in vivo fungicidal effect of PCW nanoflowers is confirmed on a murine skin fungal infection model and a murine fungal keratitis model. Fungal infections can be debilitating and life-threatening. Here, the authors report a fungicidal strategy by the combination of cell wall digestion and cuproptosis using lywallzyme-assembled copper-phenolic nanoflowers demonstrating synergistic effects in fungal infection and fungal keratitis models.