microRNA靶向递送系统的工程化构建及其在心梗治疗中的应用

MicroRNAs play an important role in biological signal pathways. Introducing exogenous microRNA mimics into cells has been proven effective in regulating cellular behaviors, such as reprograming, differentiation and proliferation, thereby holding promise to provid a new type of therapy for cardiac regeneration. However, due to the molecular characteristics of nucleic acids, how to deliver small RNA molecules efficiently to overcome biological barriers and enable silencing of specific gene in cardiac cells still remain the bottleneck of RNAi therapeutics. This project aims to exploit how to develop an efficient and targeted delivery system for small RNAs and enhance cardiac regeneration for treating myocardial infarction. A dendrimeric delivery system will be developed to enable high efficiey in transfecting cardiac cells with to microRNAs.The interactions between the delivery system and different types of cells in cardiac tissue will be investigated to promote the targeting effects of the delivery systems in heart. Furthermore, targeted microRNA delivery will be combined with hydrogel matrices and stem cell therapy to build new types of therapeutic systems, which will be tested in the myocaridac infarction animal models for improvement of cardiac tissue regeneration and functioncal recovery. The project will not only pave the way for estalishing key knowlowdege and technologies for delivering and utilizing microRNAs, but will also open new doors to treating cardiac infarction.

非编码微小RNA（microRNA）在生物体信号网络中发挥着重要作用，已被证明参与调控心肌细胞/心肌组织干细胞功能，为心肌组织再生治疗开辟了重要的新方向。然而由于核酸类的分子特征，如何有效递送小RNA，使其在心肌组织发挥特异性作用是小RNA类治疗物开发面临的瓶颈问题之一。本项目拟围绕心梗后心肌的再生治疗，系统探索如何构建具有高效转染效率和靶向性的microRNA模拟物递送系统，使其具有促进心肌组织再生的能力。将在一种树枝状高分子递送系统设计基础上，优化非病毒递送系统传导小RNA的效率。同时将研究载体材料与心肌组织中不同细胞的相互作用，实现靶向载体的构建。并结合水凝胶支架材料及干细胞等治疗系统，在心梗动物模型中研究microRNA递送对心肌再生和心肌功能恢复的实质效果。项目的实施将为小RNA治疗物递送系统的构建探明关键理论和技术路线，同时将有望开辟心梗治疗的新途径。

开发能靶向递送小RNA的纳米给药系统在心梗治疗中有着重要的发展前景。本项目通过转基因动物、活体成像等先进手段，解析了纳米递送系统在心肌组织中递送小RNA的相关过程、机制及转染效率，确立了纳米递送系统与心肌组织中与不同类群细胞相互作用的程度和特征。在此基础上，进一步探索了新型、具有靶向递送性能的纳米给药系统的设计原理。已开发的基于树枝状高分子材料的小RNA纳米递送在向心肌细胞递送siRNA和心肌组织再生机制研究中得以深入应用。同时基于细胞膜的新型材料有可能特异结合炎症细胞并利用炎症细胞循环和损伤响应的功能实现对小RNA实现主动靶向递送，为进一步发展先进的靶向心肌组织的小RNA药物递送系统奠定了基础。