Self-Assemblied Fe-Zol Nanoparticles In Neutrophils Promote Osteonecrosis Progression

To explore the mechanisms of bisphosphonate-related osteonecrosis of jaw (BRONJ) based on plasticity and iron metabolism in jawbone neutrophils. Jawbone and femur injury model with/without Zoldronate injection was established in C57BL/6 mice, approved by Ethics Committee. Pathological analysis included gross observation, micro-CT and histological examination. Neutrophils were extracted from intact femur or at trauma for transcriptomic, metabolomic, phenotypic and effector function analysis. Iron loads were quantified by Elabscience® kit and FerroOrange staining. Fe-ZOL nanoparticles (FZ-NPs) was observed through transmission electron microscopy. Mice were injected with FZ-NPs, FZ-NP-loaded neutrophils or Deferoxamine to validate the pathogenicity of FZ-NPs. Student’s t-tests and ANOVA were used to determine significant difference. Healing of jawbone and femur injury induced distinct changes in the transcriptomic, metabolomic, and effector function profiles of bone marrow neutrophils distant from injury. Zoledronate induced an anti-healing phenotype with enhanced release of oxidized mtDNA-containing-NETs in jaw-injury-induced but not femur-injury-induced neutrophils, which were further exacerbated at local injury site, related to the high iron load specifically found in jawbone neutrophils. FZ-NPs was widely found in neutrophils at BRONJ sites and injection of FZ-NPs can induced more severe osteonecrosis, while iron chelation suppressed the BRONJ progression. The jawbone-injury-induced neutrophil plasticity and the self-assemblied FZ-NPs in neutrophils were related to the pathogenesis of BRONJ. Targeting iron pathways or nanoparticle interactions offers novel therapeutic avenues for BRONJ.