Background: Invasive aspergillosis (IA) is a deadly fungal lung infection. Antifungal resistance and treatment side effects are major concerns. Iron chelators are vital for IA management, but systemic use can cause side effects. We developed nanoparticles (NPs) to selectively deliver the iron chelator deferasirox (DFX) for IA treatment. Methods: DFX was encapsulated in poly(lactic-co-glycolic acid) (PLGA) NPs using a single emulsion solvent evaporation method. The NPs were characterized by light scattering and electron microscopy. DFX loading efficiency and release were assessed spectrophotometrically. Toxicity was evaluated using SRB, luciferase, and XTT assays. Therapeutic efficacy was tested in an IA mouse model, assessing fungal burden by qPCR and biodistribution via imaging. Results: DFX-NPs had a size of ~50 nm and a charge of ~−30 mV, with a loading efficiency of ~80%. Release kinetics showed DFX release via diffusion and bioerosion. The EC50 of DFX-NPs was significantly lower (p < 0.001) than the free drug, and they were significantly less toxic (p < 0.0001) in mammalian cell cultures. In vivo, NP treatment significantly reduced Af burden (p < 0.05). Conclusion: The designed DFX-NPs effectively target and kill Af with minimal toxicity to mammalian cells. The significant in vivo therapeutic efficacy suggests these NPs could be a safe and effective treatment for IA.

BACKGROUND. Invasive aspergillosis (IA) is a deadly fungal lung infection. Antifungal resistance and treatment side effects are major concerns. Iron chelators are vital for IA management, but systemic use can cause side effects. We developed nanoparticles (NPs) to selectively deliver the iron chelator deferasirox (DFX) for IA treatment. METHODS DFX was encapsulated in poly(lacticco‐ glycolic acid) (PLGA) NPs using a single emulsion solvent evaporation method. NPs were characterized by light scattering and electron microscopy. DFX loading efficiency and release were assessed spectrophotometrically. Toxicity was evaluated using SRB, luciferase, and XTT assays. Therapeutic efficacy was tested in an IA mouse model, assessing fungal burden by qPCR and biodistribution via imaging.RESULTS DFX‐NPs had a size of ~50nm and a charge of ~‐30mV, with a loading efficiency of ~90%. Release kinetics showed DFX release via diffusion and bioerosion. The EC50 of DFX‐NPs was significantly lower (p<0.001) than the free drug, and they were significantly less toxic (p<0.0001) in mammalian cell cultures. In vivo, NPs treatment significantly reduced Af burden (p<0.05). CONCLUSION The designed DFX‐NPs effectively target and kill Af with minimal toxicity to mammalian cells. The significant in vivo therapeutic efficacy suggests these NPs could be a safe and effective treatment for IA.