Synthetic Lethal Therapy Based on Dimorphism for Systemic Infection of Drug‐Resistant <i>Candida albicans</i>

Systemic infections of Candida albicans are dire, with a mortality rate reaching 60%. The transformation between the yeast and hyphae states of C. albicans resists existing medications and the body's immune defenses. Some currently available drugs only inhibit the growth of the yeast-form of C. albicans. Therefore, a synthetic lethal therapy that leverages the dimorphism of C. albicans is developed. This therapy utilizes rapamycin to eliminate yeast-like C. albicans through the mammalian target of rapamycin pathway. Simultaneously, deferasirox restricts iron resources, thereby inhibiting polarization and hyphae formation. As a result, C. albicans cannot evade the lethal effects of drugs and immune cells by undergoing morphological transformations. Furthermore, inspired by the recognition process of fungi by macrophages, macrophage membranes with high expression of dectin-1 are utilized to deliver rapamycin and deferasirox. The synthetic lethal therapy based on dimorphism significantly improves the survival rate of mice with systemic infections, thereby offering a promising strategy for treating drug-resistant C. albicans infections.