聚多肽材料抑制游离核酸引起的脑创伤炎症反应

Traumatic brain injury is usually combined with severe inflammatory response which can cause a secondary injury to brain tissue and neural functions. Recent studies show that inflammation is related to the high concentration of cell-free DNA that released from the damaged tissue and the dying cells. These cell-free DNA could stimulate microglia and induce the production of inflammation factors. In spite of several reports utilizing cationic polymers to scavenge cell-free DNA and inhibit inflammatory response, there has been no reports focusing on the brain inflammation. Moreover, the types of the chosen materials are very limited, with lack of biodegradation and biosafety properties. Many basic issues need to be answered, such as how materials effectively and selectively bind cell-free DNA and how material-DNA complexes avoid the uptake and recognition of immune cells, etc. These questions need to be explored by the subtle designation of materials. In this project, a series of cationic polypeptide nanomaterials will be designed, synthesized, and utilized to scavenge cell-free DNA and inhibit inflammatory response. We will study the influence of peptide composition and structure on the its circulation stability, inflammation targeting, DNA binding capability and neuro-inflammation inhibition effect. We will explore the mechanism on how materials block the activation of immune response and understand the connection between material structure and its anti-inflammation effect, for the purpose of developing new, effective strategies to combat inflammation after traumatic brain injury.

创伤性脑损伤一般会伴随严重的炎症反应，对脑组织和神经功能造成二次损伤。近年来的研究表明，炎症反应与受损组织和坏死细胞所释放的高浓度游离核酸有关。游离核酸能够刺激小胶质细胞产生免疫炎症因子，进而导致过度的免疫炎症反应。虽然目前已有通过阳离子聚合物清除游离核酸，并抑制炎症的尝试，但尚无针对脑创伤炎症的报道，而且所用聚合物种类匮乏，缺乏生物降解和安全性。其中很多基本问题尚不清楚，如聚合物如何高效选择性结合游离核酸、如何避免免疫细胞摄入和识别等，亟需从材料的设计方面做深入探索。本项目拟设计合成一系列阳离子聚多肽自组装纳米材料，对游离核酸进行结合及清除，以达到减轻炎症的目的。通过研究聚多肽材料的组分、结构等因素对其体内循环稳定性、炎症部位靶向性、核酸结合能力、抑制神经炎症方面的影响，探索材料阻断核酸免疫激活的机制，建立材料结构与抗炎效果的联系，为开发新型脑损伤抗炎高分子材料提供新思路。

创伤性脑损伤（TBI）是神经外科最常见的急危重症之一，同时伴随有严重的炎症反应，对脑组织和神经功能造成二次损伤。近年来的研究表明，炎症反应与受损组织和坏死细胞所释放的高浓度游离核酸（cfDNA）有关。目前通过阳离子聚合物清除cfDNA来抑制炎症的策略已获得了广泛研究，包括用于系统性红斑狼疮、类风湿性关节炎以及慢性伤口炎症治疗中并取得了一定的治疗效果。为探究阳离子聚合物在治疗TBI炎症方面的潜在应用能力，本项目制备了一系列新型两亲性阳离子嵌段聚氨基酸共聚物及其自组装纳米颗粒，并探究了该阳离子纳米颗粒(cNPs)的理化性能、体内分布、生物安全性以及针对TBI炎症反应的治疗效果。经本项目研究发现，项目中所设计合成的cNPs为高级囊泡结构，其尺寸可由聚合物亲疏水嵌段的比例调控，亲水性聚肌氨酸的引入不仅能够促进cNPs与DNA的结合，还显著地提高了其生物相容性。经优化筛选得到的cNPs对cfDNA具有较强的吸附能力，并能有效抑制cfDNA刺激免疫细胞产生炎症因子。将cNPs应用于TBI小鼠模型发现静脉注射的cNPs能够积累在脑组织炎症部位并有效抑制脑部炎症因子的表达，对小鼠神经功能恢复起到促进作用。.本项目结合了高分子可控聚合与免疫调控研究，推动高分子合成化学与生物医学学科交叉的发展，为探索材料抗炎构效关系，开发新型脑损伤抗炎高分子材料有重要的指导意义。