Radiation‐induced lung injury (RILI) is a potentially fatal and dose-limiting complication of thoracic cancer radiotherapy. However, effective therapeutic agents for this condition are limited. Here, we describe a novel strategy to exert additive effects of a non-erythropoietic EPO derivative (ARA290), along with a free radical scavenger, superoxide dismutase (SOD), using a bioengineered nanoreactor (SOD@ARA290-HBc). ARA290-chimeric nanoreactor makes SOD present in a confined reaction space by encapsulation into its interior to heighten stability against denaturing stimuli. In a RILI mouse model, intratracheal administration of SOD@ARA290-HBc was shown to significantly ameliorate acute radiation pneumonitis and pulmonary fibrosis. Our investigations revealed that SOD@ARA290-HBc performs its radioprotective effects by protecting against radiation induced alveolar epithelial cell apoptosis and ferroptosis, suppressing oxidative stress, inhibiting inflammation and by modulating the infiltrated macrophage phenotype, or through a combination of these mechanisms. In conclusion, SOD@ARA29-HBc is a potential therapeutic agent for RILI, and given its multifaceted roles, it may be further developed as a translational nanomedicine for other related disorders.

放射诱发的肺损伤 (RILI) 是一种潜在的致命性和剂量限制性胸癌放疗并发症。然而，这种病症的有效治疗剂是有限的。在这里，我们描述了一种使用生物工程纳米反应器 (SOD@ARA290-HBc)发挥非红细胞生成EPO衍生物 (ARA290) 和自由基清除剂超氧化物歧化酶 (SOD)相加作用的新策略。ARA290-嵌合纳米反应器通过封装使SOD存在于有限的反应空间中进入其内部以提高对变性刺激的稳定性。在 RILI 小鼠模型中，SOD@ARA290-HBc 的气管内给药显示出显着改善急性放射性肺炎和肺纤维化。我们的研究表明，SOD@ARA290-HBc 通过防止辐射诱导的肺泡上皮细胞凋亡和铁死亡、抑制氧化应激、抑制炎症和调节浸润的巨噬细胞表型，或通过这些机制的组合来发挥其辐射防护作用。总之，SOD@ARA29-HBc 是一种潜在的 RILI 治疗剂，鉴于其多方面的作用，它可能会被进一步开发为其他相关疾病的转化纳米药物。