"干细胞纳米粒”神经修复给药系统的研究

Nervous system remodeling is an effective strategy for early intervention in the treatment of neurodegenerative diseases. In this project, inspired from “HDL bionics”, apolipoprotein A-I was reversibly bound to phenylboric acid-rich cationic polymers, together with miR-124 compress (electrostatic interaction) and all-trans retinoic derivative (adRA) incorporation (coordination) to complete adRA/miR-124 co-loaded multi-responsive nanoparticles. Moreover, homologous adipose-derived mesenchymal stem cells (ADSCs) were used as cooperated drug carrier to co-construct “stem cell-nanoparticles” drug delivery system for neurorestoration by targeted incubation. By virtue of potent BBB permeability and highly homing to injured region of ADSCs, the system was recruited to degenerative neuron. Triggered by low pH and high ROS, adRA and miR-124 were programmed release from the nanocarrier and synergistically co-regulate directional differentiation of ADSCs for efficient degenerative neuron restoration. The “stem cell-nanoparticles” is of highly bionic safety, potent BBB permeability, independence on pathogenesis, targeted and triggered drug release, and directional neurorestoration. The project focuses on construction and evaluation of “stem cell-nanoparticles” drug delivery system, as well as drug efficacy research in vivo and in vitro. Moreover, efficacy of multi-controlled and triggered drug release, and mechanism of targeted regulation of neuronal regeneration and restoration were also explored, which would provide a novel design mode for treatment of neurodegenerative diseases and a novel solution for efficiently directional differentiation of stem cell therapy.

重塑功能障碍神经系统是早期干预治疗神经退行性疾病的有效方法。本项目基于“HDL仿生学”将载脂蛋白apoA-I可逆键合于富苯硼酸阳离子聚合物，通过静电压缩miR-124、配位承载全反式维甲酸衍生物（adRA），构建多控响应型纳米粒；并以同源脂肪间充质干细胞（ADSCs）为共载体模型，经靶向孵育共建“干细胞纳米粒”神经修复给药系统。该系统将借助ADSCs的BBB高渗性和受损部位高聚性募集于退行神经元，且由低pH和ROS触发程序式释放adRA和miR-124，协同调控ADSCs定向分化，实现退行神经元高效修复。该系统具有高度仿生安全、BBB高渗透、非致病机制依赖、药物定位触控及退行神经定向修复等特性。课题重点围绕系统构建、评价和体内外药效展开研究，并探讨该系统多控响应释药效能和定向调控神经元再生修复机制，为神经退行性疾病提供一种全新治疗模式，为干细胞治疗的高效定向分化提供一种全新解决方案。

针对神经退行性疾病不可逆神经损伤的病理特征，干细胞移植疗法已成为当前实现神经再生修复的首选策略，却受限于其神经分化效率低导致的疗效不足。为此，本项目以阿尔兹海默症（AD）等神经退行性疾病为模型，构建富苯硼酸多控智能载体（RPP）共载全反式维甲酸衍生物（atRAN）与miR-124，表面配位键合载脂蛋白apoA-I，形成的纳米粒经体外孵育间充质干细胞（MSCs）构建了“干细胞纳米粒”神经修复给药系统。该系统经移植入脑后，纳米粒在胞内低pH、高ROS的微环境信号触发下，程序式速释化学药物atRAN与miR-124，协同调控MSCs定向神经分化。本项目通过细胞水平及在体药效学研究，验证了纳米粒具有温和高效的转染特性及多控响应的释药效能，并进一步探讨了MSCs定向神经分化及其神经修复治疗机制，从根本上实现了针对AD脑内障碍神经系统的神经再生与重塑。本研究有助于解决当前AD等神经退行性疾病治疗中存在的药物疗效差、新药开发难度大等问题，为设计有效的临床治疗方案提供了新方法和新思路。本项目超额完成了预期研究任务，在国内外核心期刊发表论文18篇，其中SCI收录论文15篇（10篇IF＞10），授权专利14项，申请专利10项；培养博士后1名，博士研究生3名、硕士研究生18名。