Macrophage membrane-camouflaged diatomic nanozymes combined with FLASH radiotherapy reprogram tumor-associated macrophages to boost antitumor immunity

Despite the excellent normal tissue protection and immunomodulatory potency of ultra-high dose-rate FLASH radiotherapy (Flash-RT), CD47-mediated tumor immune escape severely restricts its clinical anti-tumor immune efficacy. To address this critical therapeutic bottleneck, we fabricated a novel macrophage membrane-biomimetic Cu/Ru dual-atom nanocatalyst (CRM) for synergistic Flash-RT tumor immunotherapy. Equipped with abundant macrophage membrane-derived SIRPα, intravenously injected CRM achieves long-term immune camouflage and accurate tumor accumulation, which efficiently blocks the CD47 “don’t eat me” immune checkpoint signal. The uniform Cu/Ru dual-atom active sites act as high-performance radiosensitizers to significantly amplify intracellular reactive oxygen species generation under Flash irradiation, triggering severe tumor cell apoptosis and reprogramming metabolic phenotypes of tumor-associated macrophages (TAM). This synergistic combinatorial strategy effectively reverses immunosuppressive M2 polarization of TAM, robustly enhances macrophage-mediated tumor phagocytosis, and activates durable systemic anti-tumor immune responses. In vitro and in vivo experimental results consistently confirm that CRM remarkably boosts the anti-tumor efficacy of Flash-RT, efficiently suppressing primary tumor growth and distant tumor metastasis. This study presents a novel and reliable dual-atom biomimetic nanocatalytic platform to optimize FLASH radiotherapy-based tumor immunotherapy for solid tumors.