基于巨噬细胞膜靶向性的抗菌药物递送体系治疗肺炎克雷伯菌肺炎的应用及机制研究

Pulmonary infection is one of the most common complications after burn, in which Klebsiella pneumoniae (Kpn) is highly resistant and has a high mortality rate. At present, the clinical use of polymyxin B in the treatment of Kpn pneumonia has poor effect due to the lack of lung targeting and causes multiple organ toxicity. Therefore, how to enhance the lung targeting of polymyxin B is urgently needed to be solved. Previously our research team used the weakly acidic characteristics of the bacterial infection site to prepare antibacterial materials targeting the infected sites, indicating that the antibacterial drug delivery system based on the microenvironment of the infected site is expected to achieve targeted drug delivery. It has been reported that pulmonary vascular endothelial cell targeting peptides can specifically bind to pulmonary vascular endothelial cells. In addition, the microenvironment of the infected site expresses ICAM-1 and CCL2, which can catalyze the targeting of the macrophage-encapsulated nanomaterials to the infected site. The bacterial pre-stimulated macrophage membrane wrapping material can further enhance the targeting of the infected site. This project aims to construct a macrophage membrane with lung infection targeting lung antigen pre-stimulation and pulmonary vascular endothelial cell targeting peptide, and use it to encapsulate supramolecular gelatin with controlled release of polymyxin B. The results are expected to provide a new treatment strategy for Kpn pneumonia.

肺部感染是烧伤后最常见的内脏并发症，肺炎克雷伯菌肺炎耐药性强且病死率高。目前临床上使用多粘菌素B治疗肺炎克雷伯菌肺炎因缺乏肺部靶向性而效果不佳并引起多器官毒性，如何增强多粘菌素B的肺部靶向性是亟待解决的问题。本研究团队既往利用细菌感染部位弱酸性特点制备了靶向感染部位的载抗生素纳米抗菌材料，表明基于感染部位微环境特点设计抗菌药物递送体系有望实现抗生素的靶向给药。既往文献报道，肺血管内皮细胞靶向肽可以特异性与肺血管内皮细胞结合。此外感染部位微环境高表达ICAM-1和CCL2，可以趋化巨噬细胞膜包裹的纳米材料靶向感染部位，利用细菌预刺激的巨噬细胞膜包裹材料可以进一步增强其感染部位靶向性。本项目拟构建细菌预刺激和肺血管内皮细胞靶向肽双重修饰的具有肺部感染靶向性的巨噬细胞膜，并利用其包裹可控释放多粘菌素B的超分子明胶，从而实现多粘菌素B的肺部感染靶向给药。研究结果有望为肺炎克雷伯菌肺炎提供新策略。

细菌感染给全球带来巨大的经济负担，细菌感染会导致感染皮肤和脏器的严重损伤和持续性炎症，构建可以靶向感染部位的纳米药物递送体系治疗皮肤和脏器感染是一种有效策略。本项目基于细胞膜表面受体蛋白的特性和生物学功能，设计制备了多种细胞膜包裹的纳米药物递送体系。首先，本项目设计和制备了具有靶向细菌感染部位并且能够吸附细菌毒素的细胞膜包裹的具有光热杀菌作用的介孔硅酸铜纳米抗菌药物递送体系（CSO@PM）用于治疗皮肤细菌感染，CSO@PM可通过细胞膜上的甲酰基肽受体靶向到细菌表面，从而实现高效光热杀菌。CSO@PM能够吸附中和感染部位细菌产生的内毒素，降低感染部位的炎症水平，加速感染创面的愈合。为实现靶向损伤脏器部位的药物递送，本项目合成制备了细胞膜包裹的中空多孔硅锰纳米材料（TMSN@PM），TMSN@PM可通过细胞膜上的GPIb/IIIa糖蛋白复合物与损伤脏器部位暴露的胶原蛋白结合，从而实现高效靶向脏器递送药物。在损伤脏器炎症部位过度升高的ROS和偏酸性微环境中，TMSN@PM可以清除过量的ROS并快速降解释放Mn2+，从而在降低脏器炎症水平的同时可以通过磁共振实时可视化监测脏器部位的ROS和炎症水平。在此基础上，本项目探索构建了巨噬细胞膜包裹的装载抗生素的超分子明胶纳米抗菌材料，用于靶向治疗肺部细菌感染。本项目在执行过程中发现，不同亚型巨噬细胞的细胞膜存在不同的生物学功能，基于此本项目还探索了不同亚型巨噬细胞膜包裹的聚多巴胺纳米粒子对炎症的调控和糖尿病创面修复的作用。本项目的开展为细胞膜包裹的纳米材料用于治疗皮肤和脏器的炎症和感染打下了基础，也为基于细胞膜包裹纳米材料技术的仿生纳米药物递送体系的设计提供了一定的理论支撑。