造血系统损伤可能会导致骨髓造血功能异常，引发骨髓增生异常综合征、再生障碍性贫血、白血病等血液系统疾病。随着电离辐射（Ionizing radiation, IR）在医学诊断和肿瘤放疗领域的广泛应用，人类意外暴露的风险不断增加。放射性接触是导致造血功能异常的重要因素，其主要原因是IR诱导大量活性氧（Reactive oxygen species, ROS）的产生，从而导致造血系统内的细胞和蛋白质受到损伤。目前，治疗方法主要依赖于造血生长因子和干细胞移植。然而，高水平的ROS病理微环境限制了细胞因子和干细胞的功能发挥。基于现状，我们提出了将抗氧化治疗与细胞因子、干细胞治疗相结合的策略，旨在改善氧化微环境的同时刺激造血，促进造血系统的恢复。

本研究首先以刺激响应性高分子材料为药物载体，联合抗氧化治疗和造血生长因子改善辐射诱导的造血系统损伤。鉴于辐射后病理微环境ROS水平较高，本研究引入可在过氧化氢（Hydrogen peroxide，H₂O₂）下发生断裂的过氧草酸酯键，合成了三臂聚（乳酸-共乙醇酸）-聚（乙二醇）（3s-PLGA-PO-PEG），由此构建了ROS响应性促红细胞生成素（Erythropoietin，EPO）纳米递送系统（EPO NPs）。该递送系统一方面提高了生物大分子药物生物利用度，延长EPO体内作用时间；另一方面清除体内过量ROS，避免了进一步氧化损伤，并提供更好的药物作用环境。研究构建了辐射诱导造血系统损伤模型，EPO NPs可明显降低IR诱导的骨髓细胞ROS水平，重建骨髓造血。该研究结果表明，抗氧化治疗和造血生长因子的联合应用可多方位促进造血恢复，是一种有前景的治疗策略。

本研究进一步将抗氧化治疗与干细胞移植相结合。间充质干细胞（Mesenchymal stem cells，MSCs）具有多重功能，能够迁移至损伤部位，促进造血细胞增殖分化，支持造血重塑，并通过分泌多种细胞因子发挥免疫调节作用，促进损伤组织的修复。研究使用表没食子儿茶素没食子酸酯（Epigallocatechin-3-gallate，EGCG）和镁离子（Mg²⁺）在MSCs表面形成金属有机框架涂层（E-Mg@MSC），增强MSCs对不利环境的抵抗力。此外，E-Mg涂层通过EGCG清除过量ROS，并提供镁来促进MSCs的成骨分化，从而创造了有利的修复条件。同时，E-Mg@MSC能够持续分泌造血生长因子，并调节MSCs向辐射敏感组织迁移。体内实验显示，E-Mg@MSC显著加快了造血系统的恢复速度，并保护了多个器官免受IR损伤。进一步的机制探索发现，辐射损伤的降低可能与E-Mg@MSC减少IR触发的ROS、细胞凋亡和铁死亡有关。研究结果表明该系统提供了一种多功能涂层策略，可用于细胞表面工程推进辐射损伤的治疗。

总之，本研究针对辐射诱导造血损伤的ROS微环境，结合目前细胞因子和干细胞移植的局限性，设计了ROS响应性载体递送细胞因子或干细胞，从而改善氧化微环境，促进造血恢复，为辐射诱导的造血系统损伤提供新的治疗思路。

The injury of the hematopoietic system may lead to hematopoietic dysfunction, resulting in blood system diseases, including myelodysplastic syndrome, aplastic anemia, and leukemia. The wide application of ionizing radiation (IR) in medical diagnosis and tumor radiotherapy, has increased the risk of accidental exposure to humans. IR exposure is an important factor in hematopoietic dysfunction mostly due to the production of reactive oxygen species (ROS), which leads to cellular and protein damage in the hematological system. The current treatments mainly rely on hematopoietic growth factors and stem cell transplantation. However, the high level of ROS in the pathological microenvironment inhibits the action of cytokines and stem cells. Thus, our research proposes a strategy of combining antioxidant therapy with cytokines or stem cells, aiming to regulate the oxidative microenvironment while simultaneously fostering hematopoiesis, expediting the recuperation of the hematopoietic system.

In this study, the stimuli-responsive polymer materials were used as drug carriers to ameliorate IR-induced hematopoietic injury in combination with antioxidant therapy and hematopoietic growth factors. Given the high level of ROS in the pathological microenvironment following IR exposure, a ROS-responsive erythropoietin (EPO) nano-delivery system (EPO NPs) was created by three-arm poly(lactic-co-glycolic acid)-PO-poly(ethylene glycol) (3s-PLGA-PO-PEG), with peroxalate esters serving as hydrogen peroxide (H₂O₂)-responsive bonds. The delivery system not only improved the bioavailability of biomacromolecule medicines and prolonged EPO action time in vivo, but it also scavenged excess ROS, preventing further oxidative damage and creating a favorable environment for therapeutic efficacy. We developed IR-induced hematopoietic injury model, the EPO NPs significantly reduced the ROS level of bone marrow cells, rebuilding bone marrow hematopoiesis. The results showed that combinations of antioxidant therapy and hematopoietic growth factors could enhance hematopoietic recovery in multiple ways, indicating a promising therapeutic strategy.

This study further combined antioxidant with stem cell transplantation. Mesenchymal stem cells (MSCs) provide several roles, including the capability of migrating towards the site of injury, promoting the proliferation and differentiation of hematopoietic cells, supporting hematopoietic reconstruction, and exerting immunomodulatory effects by secreting cytokines, thus promoting tissue repair. Epigallocatechin-3-gallate (EGCG) and magnesium ions (Mg²⁺) were used to form a metal-organic framework coating on the surface of MSCs (E-Mg@MSC) to strengthen MSCs resistant to harmful stresses. In addition, the E-Mg coating scavenged excess ROS through EGCG and provided Mg²⁺ to promote the osteogenic differentiation of MSCs, creating a favorable microenvironment for repair. Also, E-Mg@MSC could consistently secrete hematopoietic growth factors and regulate homing to IR-sensitive tissues. In vivo experiments demonstrate that E-Mg@MSC significantly enhances the recovery of the hematopoietic system and protects multiple organs from damage. Further exploration of the mechanism reveals that the reduction of radiation damage may be related to E-Mg@MSC decreasing IR-triggered ROS, cell apoptosis, and ferroptosis. The results suggested that the system provides a multifunctional coating strategy that can be used for cell-surface engineering to advance the treatment of IR injury.

In conclusion, our work focused on the ROS microenvironment of IR-induced hematopoietic injury and the limitations of cytokine and stem cell transplantation. ROS-responsive carriers were designed to deliver cytokines or stem cells to regulate the oxidative microenvironment, promote hematopoietic recovery, and provide new therapeutic approaches for IR-induced hematopoietic injury.