Bismuth-coordinated nanocomplex drives M2 macrophage polarization via mitochondrial reprogramming against invasive aspergillosis

Invasive aspergillosis has a high mortality rate, and existing antifungal drugs face the dual challenges of drug resistance and immune evasion. In this study, we designed a bismuth-coordinated self-assembled nanocomplex (Bi@CBD-DFO) constructed by fusing a chitin-binding domain, the STING-activating peptide mN18, and the siderophore mimetic deferoxamine, which formed regular spherical particles driven by bismuth ions, possessing triple functions of fungal targeting, iron competition, and STING pathway activation. After being taken up by macrophages, this nanocomplex repaired the Aspergillus fumigatus -damaged mitochondrial network in an OXPHOS-dependent manner, restored electron transport chain complex I/II activity and TCA cycle flux, activated the pentose phosphate pathway, reversed infection-induced M1 polarization, and promoted M2-like phenotype transformation. In vitro experiments showed that Bi@CBD-DFO concentration-dependently protected lung epithelial cells (recovery to 74.2% at 0.4 mg/mL) with no obvious cytotoxicity; transcriptomics and metabolomics confirmed its systemic regulation of mitochondrial metabolic reprogramming at multiple levels. Mouse aerosol administration results indicated that this nanocomplex did not affect major peripheral blood routine parameters but significantly increased monocyte counts, suggesting in vivo immune activation. This study proposes a synergistic therapeutic strategy of “targeting iron metabolism − restoring host mitochondrial function − remodeling antifungal immunity,” providing experimental evidence for immunometabolic intervention in invasive aspergillosis.