Biocatalytic Radioprotection via a RBC-Hitchhiked Ruthenium Complex: A Smart Navigation System Ameliorates Radiation-Induced Lung Injury

Radiation-induced lung injury (RILI) is a serious complication of radiotherapy (RT) for thoracic malignancies. Complex pathological microenvironments, characterized by high levels of reactive oxygen species (ROS), persistent inflammatory responses, and immune dysregulation, drive the development of early radiation pneumonitis (RP) and late fatal radiation pulmonary fibrosis (RPF). The clinical treatment of RILI is severely constrained by the unsatisfactory outcomes and substantial side effects of its sole current option, systemic glucocorticoids. Herein, we propose a red blood cell (RBC) hitchhiking smart navigation system for a ruthenium (Ru)-based artificial antioxidase, designated as RBC@Ru(bda)[Me-bpy]2[PF6]2 (RBC@RBM). This system effectively evades recognition and clearance by the mononuclear phagocytic system, enabling prolonged circulation and enhanced drug enrichment at the injury site, thereby facilitating superior biocatalytic regeneration and repair. Furthermore, the highly asymmetric six-coordination with open site configuration of RBM promotes swift proton-electron transfer, thereby demonstrating efficient, broad-spectrum, and robust ROS scavenging capabilities. Our studies demonstrate that RBC@RBM maintains alveolar epithelial cell viability and vascular integrity and exhibits superior repair function in elevated ROS environments, thereby simultaneously modulating the inflammatory microenvironment and preserving alveolar-capillary barrier function. We believe synthesizing such potent biocatalytic materials with antioxidase-mimetic properties will offer a promising pathway for the treatment of RILI.