Effective treatment of systemic candidiasis by synergistic targeting of cell wall synthesis

Ju Yeon Chung, Yoon-Kyoung Hong, Eunhee Jeon, Seungju Yang, Ayoung Park, Ralph Weissleder, Yong Pil Chong () and Hyun Jung Chung ()
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Ju Yeon Chung: Korea Advanced Institute of Science and Technology
Yoon-Kyoung Hong: University of Ulsan College of Medicine
Eunhee Jeon: University of Ulsan College of Medicine
Seungju Yang: Korea Advanced Institute of Science and Technology
Ayoung Park: Korea Advanced Institute of Science and Technology
Ralph Weissleder: Massachusetts General Brigham
Yong Pil Chong: University of Ulsan College of Medicine
Hyun Jung Chung: Korea Advanced Institute of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Fungal infections pose a serious threat to global human health fueled by the increase in immunosuppressive therapies, medical implants, and transplantation. The emergence of multidrug resistance with limited options of current antifungal drugs are a further constraint. There is thus a clear and unmet need to identify therapeutic targets and develop alternative classes of antifungal agents. Here, we hypothesize that dual targeting of key regulatory genes of fungal cell wall synthesis (FKS1 encoding β−1,3-glucan synthase and CHS3 encoding chitin synthase) can synergistically inhibit fungal growth. Based on iterative designs, we generate a small library of fungal-targeted nanoconstructs, and identify a lead construct (FTNx) that shows preferential accumulation in fungal cells over mammalian cells and leads to prominent antifungal effects in vitro. We further show that FTNx is highly effective in a mouse model of disseminated candidiasis, demonstrating diminished fungal growth and enhanced survival rate. This strategy appears promising as an effective treatment for fungal infections in mammalian hosts.

Date: 2025
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DOI: 10.1038/s41467-025-60684-7

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