Spatiotemporal iron-hijacking hydrogel reprograms host-pathogen iron homeostasis for fungal keratitis therapy

Severe infections caused by opportunistic fungal pathogens like Candida albicans remain a major clinical challenge, exemplified by vision-threatening fungal keratitis (FK). Targeting host-pathogen iron competition offers a promising antifungal strategy. Here, we identify a vicious cycle in human FK, where iron overload-driven host ferroptosis promotes fungal proliferation and inflammation. To disrupt this, we develop a spatiotemporally controlled gallium-deferiprone (Ga-DFP) composite hydrogel (PGaDH) that reprograms host-pathogen iron homeostasis through an iron-hijacking strategy. Specifically, PGaDH enables rapid DFP release to induce fungal iron starvation and activate iron acquisition pathways, followed by slow Ga³⁺ release that mimics Fe³⁺ and disrupts fungal iron-dependent energy metabolism. Concurrently, PGaDH suppresses host ferroptosis, fungal-induced oxidative stress, and mitogen-activated protein kinase (MAPK)/NF-κB-mediated inflammation. In mouse and rabbit FK models, PGaDH shows prolonged ocular retention, potent antifungal efficacy, and reliable safety. These findings establish a dual iron-hijacking platform with translational potential for fungal and related diseases.