Abstract

Ionizing radiation-induced damage to the hematopoietic system is largely driven by STING activation-promoted M1 macrophage polarization and its resultant inflammation. However, effective suppression of pro-inflammatory macrophage polarization for treating radiation-induced hematopoietic stem cell injury is largely hindered by the inherent physiological barriers of bone marrow-targeted drug delivery. In this study, we develop a STING nanoinhibitor composed of poly(lactic- co -glycolic acid) nanoparticle loaded with a STING inhibitor and surface-coated senescent neutrophil membrane for targeted treatment of ionizing radiation-induced hematopoietic injury. Our STING nanoinhibitor can home to bone marrow via the CXCR4/SDF-1 axis and be phagocytosed by macrophages to shift activated pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype through suppressing cGAS-STING signaling, and this STING inhibition can further reduce radiation-induced reactive oxygen species (ROS) accumulation to reduce M2-to-M1 macrophage polarization. In irradiation-treated mouse models, the STING nanoinhibitor preferentially accumulates in bone marrow to alleviate pancytopenia, preserve bone marrow architecture, and accelerate hematopoietic recovery while avoiding significant side effects. This study highlights the targeted modulation of bone marrow macrophages as a promising strategy for promoting hematopoietic cell recovery from radiation-induced injury.