可视化纳米酶调控神经炎性微环境治疗难治性癫痫

About 30% of the patients with epilepsy are difficult to be effectively controlled by antiepileptic drugs and are defined as refractory epilepsy. Over-produced ROS in refractory epilepsy foci can polarize resting microglia into pro-inflammatory phenotype, which secreting large amounts of inflammatory mediators to trigger the inflammatory cascade, shaping the inflammatory microenvironment, inducing abnormal firing of neurons, and ultimately promoting the development of refractory epilepsy foci. Due to the important role of microglia in the development of refractory epilepsy, this project aims to construct a paramagnetic ultra-small nanozyme that can simultaneously, efficiently and cyclically eliminate various types of ROS. The nanozyme can cross the damaged blood-brain barrier in epilepsy foci, eliminate excess ROS, inhibit redox-sensitive calcium-permeable nonselective cation channel TRPM2, prevent abnormal calcium influx and activation of NF-κB inflammatory signaling pathway, inhibit pro-inflammatory phenotypic polarization of microglia, improve the inflammatory microenvironment of epileptic foci, and block abnormal neuronal discharge to improve the treatment of refractory epilepsy. In addition, the magnetic resonance imaging property of nanozyme can be used to assess brain entry efficiency, foci content and retention time in vivo, and provide useful information for disease treatment. This proposed project is a new strategy to improve the effect of refractory epilepsy treatment by modulating the phenotypic polarization of microglia and ameliorating the inflammatory microenvironment, which to be of great clinical value in improving the quality of life of patients with refractory epilepsy.

约30%癫痫患者难以被抗癫痫药物有效控制而被定义为难治性癫痫。病灶中过量生成的活性氧（ROS）可驱动静息态小胶质细胞极化为促炎表型，分泌大量的炎性介质触发炎症级联反应、塑造炎性微环境，诱导神经元异常放电，最终推动难治性癫痫病灶发展。鉴于小胶质细胞在难治性癫痫进程中的关键作用，本项目拟构建可同时、高效、循环消除多种类型ROS的顺磁性超小粒径纳米酶。其跨越病灶区域受损血脑屏障，消除过量ROS，抑制氧化还原敏感的钙渗透非选择性阳离子通道（TRPM2），阻止钙离子异常内流和NF-κB炎症信号通路活化，抑制小胶质细胞促炎表型极化，改善癫痫病灶炎性微环境，阻断神经元异常放电，提高难治性癫痫治疗效果。此外，纳米酶的磁共振成像性能可用于在体评估入脑效率、病灶含量和存留时间，为疾病治疗提供有益信息。本项目提出调控小胶质细胞表型极化改善炎症微环境提高难治性癫痫疗效的新策略，对提高患者生存质量具有重要临床价值。

病灶部位过量蓄积的活性氧诱发的不可控炎症造成的组织损伤驱动癫痫、炎症性肠病等多种炎症相关疾病的发生发展。由免疫细胞、细胞因子、活性氧等构成的炎性微环境在其中扮演着重要作用，是介导炎症性疾病进展或愈合的关键协调者。因此，我们提出了调控炎症微环境治疗炎症性疾病的科学假说。本项目以改善炎症微环境为目标，以活性氧为治疗靶点，主要进展包括：（1）构建了具有增强MRI成像能力和多种拟酶活性的可视化多功能纳米酶，可增强癫痫病灶的MRI信噪比，同时通过消除活性氧调控小胶质细胞表型极化改善炎症微环境提高癫痫的治疗作用。（2）利用纳米酶同时高效清除过氧化氢、超氧阴离子和羟自由基等活性氧的作用，消除炎症性肠病病灶部位过量蓄积的活性氧，抑制NF-κB和STAT3信号通路的激活，降低促炎性巨噬细胞和CD4+ T细胞的比例，改善炎症微环境，实现炎症性肠病的治疗作用。（3）利用纳米酶调节氧化磷酸化和有氧糖酵解的和消除活性氧的作用，减轻肾脏氧化应激治疗肾纤维化。总之，项目围绕癫痫、炎症性肠病等炎症相关疾病中炎症微环境调控的科学问题，构建多功能纳米酶，通过消除病灶部位过量蓄积的活性氧，调控巨噬细胞表型极化，降低促炎性细胞因子水平，改善病灶部位炎症微环境实现疾病的治疗作用，为炎症相关疾病的治疗提供一种新策略。该项目共发表论文10篇，其中SCI收录论文4篇，3篇影响因子大于9分。