ROS响应型水凝胶递送DS4V-外泌体促进卒中神经修复的研究

卒中是一种高致残率的疾病，大多数患者需依靠神经修复来恢复机体机能。前期研究证明2型小胶质细胞来源的外泌体可促进内源性神经干细胞分化为神经元，发挥神经修复作用。但神经干细胞向损伤区迁移量有限，且缺血再灌注产生的活性氧（ROS）易造成神经干细胞损伤，降低其存活率和分化效率。本项目采用D型基质细胞衍生因子DS4V修饰外泌体，赋予外泌体介导神经干细胞迁移的能力，并构建ROS响应型水凝胶负载DS4V-外泌体。该递药系统可通过降低ROS改善卒中微环境，提高神经干细胞存活率，且实现外泌体的稳定蓄积和响应释放，发挥诱导神经干细胞迁移和分化作用，增强神经修复效果。项目将系统考察DS4V-外泌体对神经干细胞的迁移诱导及定向分化能力，探讨DS4V-外泌体/水凝胶对卒中微环境的调节，明确DS4V-外泌体/水凝胶对卒中神经修复效果及机制。本项目将为应用生理响应型水凝胶作为外泌体载体对卒中治疗提供新思路及理论基础。

Most patients with ischemic stroke, a kind of disease with high disability rate, mainly need to reply on nerve repair to restore physical function. Our previous studies have shown that M2 microglia-derived exosomes could induce neural stem cells to differentiate into neurons, and achieve neural repair. However, the number of neural stem cells migrating to the injured site is limited. Moreover, reactive oxygen species (ROS) generated during reperfusion period could cause neural stem cell damage, leading to decreased survival rate and differentiation ability. Based on this, this project aims to modify exosomes with D-peptide stromal cell–derived factor-1 (DS4V), and engineer a ROS-responsive hydrogel depot to deliver this DS4V-exosome (DS4V-Exo/hydrogel). This DS4V-Exo/hydrogel could alleviate oxidative stress damage by scavenging ROS, improving survival of neural stem cells. Also, it would act as the carrier to achieve the long-time retention and responsive release of DS4V-exosome, which could mediate neural stem cell migration and directed differentiation, then enhance the therapeutic effect of stroke. This project will investigate the migrating induction and differentiation ability of DS4V-exosomes to neural stem cells, evaluate the effect of DS4V-Exo/hydrogel on stroke microenvironment, and assess its therapeutic effect and mechanism on ischemic brain tissue repair. This project would provide a new approach and theoretical basis for the application of bioresponsive hydrogel as the exosome carrier for stroke treatment.