传统的miRNA递送载体毒性明显、转染率低与病灶透过性差。本课题拟采用乳球蛋白包裹的难溶性药物纳米结晶为载体以实现miRNA的高效递送。潜在优势有：（1）绕开溶酶体，将miRNA直接递送至胞浆，实现高效转染；（2）具有活性的小分子纳米药物为载体，安全性无毒，有望突破基因给药的瓶颈；（3）实现小分子药物与基因药物的协同治疗；（4）体系构建简单、易于重现，临床应用前景广阔。运用现代制剂学手段对其进行优化和表征；结合水环境淬灭探针与活细胞成像术等探讨体系入胞、胞浆定位以及解体过程；利用粗粒分子动力学技术与膜片钳-原子力显微镜成像术研究体系的膜渗透性与细胞膜表面损伤情况；采用蛋白组学和病理学等手段评价体系的安全性。该体系将为miRNA的有效递送提供一种全新的策略，具有重大科学意义。本设计思路国内外未见报道。项目新颖性好，研究力量与科研条件具备，工作基础较扎实，已有工作结果表明本项目的可行性良好。

Toxicity, low transfection and poor tissue penetration have become the bottle neck for the clinic use of conventional carriers for miRNA delivery. Here, to improve miRNA delivery fundamentally, we will develop a new formulation with globular-protein coated nanocrystals of poorly water-soluble drugs as carriers. Its potential advantages may be included: (1) directly delivering the system into cytoplasma without entrapment in endosome-lysosome system, (2) small-molecule drug particles with activities can be completely dissolved in body without toxicity, therefore having potential to break through the bottle neck of gene delivery, (3) obtaining combined therapy of small-molecule and gene drugs, and (4) the formulation preparation is easy and reproduced, thus possessing great potential in clinic application. The system will be optimized and characterized by current pharmaceutical technology; moreover, with the help of fluorescence probe quenching in aqueous environments and live-cell CLSM imaging, the cellular entry, cytosol location, and disintegration of carriers will be explored. Via coarse-grained molecular dynamics and patch clamp-AFM technologies, the membrane penetration and disruption will be evaluated. In addition, the compatibility will be studied in the global mapping of protein expression by proteomics technology. The work will provide a new strategy for the gene delivery, which is of great scientific significance for the gene delivery. The structure and design ideas of the system are original since it has not been reported at home and abroad. We not only have strong research-force, but also possess perfect research-conditions for the project. Moreover, the base of relevant work for the project is solid and the primary results indicate its feasibility.