通过纳米递送系统的功能性组装协调siRNA的负载、输运与释放

The systemic delivery of siRNA to its target remains the biggest hurdle to clinical translation, which is also the focus issue in nanotechnology field for drug delivery. siRNA loaded nanocarriers should transport siRNA to the target cells by crossing the vascular endothelial barriers and extracellular matrixes, then be uptaken by the target cells, escape from the endosomes and release siRNA to the cytosol. In order to perform the functions of siRNA loading, delivery and release in sequence and controlledly, the nanocarriers should be multifunctional assembled and controlled in structure. For the functional assembly of the siRNA delivery systems, this project plans to assemble flexible polycations with siRNA conjugated nanoparticles by utilising the properties of the lower pH in the endosomes and the higher concentration of glutathione in the cytoplasm. This project will study the interactions of the polycations with siRNA, the nanocarriers with the tissue and cells.The effects on the delivery systems of the chain flexibility, hydrophobicity, hydrogen bonding interaction of the polycations and the deformable properties of the nanocarriers will be studied. By this work, we try to find out the efficient route to adjust the siRNA loading, delivery and release, which can provide information for the development and application of the efficient siRNA delivery systems.

siRNA的体内靶向递送是临床应用的主要瓶颈，也是纳米药物递送领域研究的热点。siRNA的递送过程包括：纳米载体负载结构刚性的siRNA，经血液循环和细胞间质输运到靶细胞，靶细胞胞吞、内涵体逃逸并释放siRNA到细胞质内。这一复杂的递送过程需要纳米递送系统协调发挥siRNA负载、输运和释放功能，而这些功能的协调发挥取决于递送系统的多功能组装和结构控制。本项目以"柔性结构的阳离子聚合物复合纳米粒化的siRNA"为基本思路，结合聚乙二醇的保护作用，利用内涵体低pH和细胞质内谷胱甘肽浓度高的特点，进行纳米递送系统的功能性组装；研究阳离子聚合物与siRNA的相互作用、递送系统与组织及细胞的相互作用；研究阳离子聚合物链柔性、电荷密度、亲疏水性、氢键作用和纳米递送系统的可变形性等结构因素对递送系统功能性的影响，探讨协调发挥siRNA负载、输运和释放功能的有效途径，为siRNA递送系统开发应用提供指导。

预期目标：建立性能优良的siRNA纳米递送系统，揭示纳米递送系统的“结构-相互作用-功能性”间的关系，获得协调发挥siRNA负载、输运和释放功能的有效途径，为靶向递送siRNA的载体设计和应用提供信息；发表8篇以上SCI收录高水平论文，申请发明专利2～3项，获得发明专利1～2项；培养硕士、博士研究生10名以上。.完成情况：主要针对两亲性非离子聚合物、两亲性阳离子聚合物及其自组装核壳结构纳米粒，进行结构设计、制备和功能性评价。从纳米粒内核结构的pH敏感性、聚阳离子段的环境敏感或疏水性等修饰、非离子亲水段的结构、纳米粒的组装方式和靶向修饰等方面，研究揭示了纳米载体的“结构-相互作用-功能性”间的关系，获得了协调发挥药物/siRNA负载、输运和释放功能的有效途径，尤其为突破细胞内siRNA转运问题提供了较好的解决方案。.在Nano Letter, Biomaterials，Nnoscale, ACS Applied Materials and Interfaces等期刊上发表SCI收录论文19篇（平均影响因子6.25，单篇最高13.7）；申报发明专利4项，其中3项获得授权。培养博士研究生11名(毕业6名)、硕士研究生5名（毕业4名）。

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