Neutrophil hitchhiking delivers STING antagonist alleviating inflammatory osteolysis

Inflammatory cascade critically exacerbates pathological bone loss, however whether aberrant STING activation is involved has not been clarified. Utilizing STING as a target to alleviate inflammatory osteolysis is worth exploring. Herein, we identified hyperactivated STING signaling as a key driver in the pathogenesis of calvarial osteolysis, suggesting that local inhibition of STING alleviated inflammation-mediated bone loss. A pivotal unmet need lies in achieving rapid organ-specific drug delivery with minimized dosage across anatomically distinct inflammatory bone compartments. We engineered neutrophils (NEs) encapsulated with poly (lactic-co-glycolic acid) (PLGA) containing STING antagonist C176 (C176/PLGA@NEs) that leveraged the innate chemotactic proficiency of bone marrow-derived NEs for inflammatory site navigation. The inflammatory transport capacity of live NEs effectively addressed challenges of high systemic doses faced by STING antagonist, and poor spatiotemporal precision in targeting osteolytic lesions. The bioengineered C176/PLGA@NEs exhibited superior biocompatibility, inflammatory chemotaxis and inflammation-responsive release, and were effective in inhibiting STING-NF-κB pathway and remodeling macrophage polarization <em>in vitro</em>. In both calvarial osteolysis and apical periodontitis models, intravenous C176/PLGA@NEs administration achieved greater bone preservation compared to free C176 at equivalent doses, accompanied by reduction in pro-inflammatory cytokines. Notably, this NE-enabled strategy demonstrated targeting efficiency, overcoming anatomical barriers. Our findings establish a paradigm for precision delivery of STING antagonists using endogenous immune vectors, offering a versatile platform to treat systemic inflammatory bone disorders. The integration of cellular tropism with stimuli-responsive nanocarriers opens avenues for adapting this biohybrid approach to other immune cells and inflammatory pathologies.