siRNA可高效专一抑制白内障的发生发展，然而如何提高其稳定性、促进其跨越角膜理化屏障并实现晶状体上皮细胞（HLECs）胞内释放，是siRNA经眼传递完成基因沉默的关键问题。前期研究发现三甲基壳聚糖（TMC）在角膜荷电环境下可发生生物黏附，通过与紧密连接蛋白作用促微粒经细胞间途径渗透至角膜上皮深层。为进一步实现HLECs靶向，结合黏合连接蛋白E-cadherin在角膜/晶状体上皮层的分布由膜间转移至胞浆的特点，本课题以磷酸钙粒子为内核构建PARP-1 siRNA高效包封非对称脂质双层纳米粒，以TMC及TMC-ADT6多肽共聚物为修饰，分别打开角膜紧密连接/黏合连接，主动靶向HLECs胞浆并释药，从动物、组织、细胞水平，调控细胞间通透性、提高siRNA靶向性及稳定性，最终完成基因经眼治疗白内障，为水溶性、大分子药物眼部吸收提供系统性通用性较强的研究模式，可进一步完善眼部给药系统的制剂学理论。

The development of cataract could be effectively inhibited by siRNA, however, how to improve the stability of the siRNA, elevate the transportation of siRNA across the corneal physiological and biochemical barriers, and achieve the cytoplasmic siRNA release in human lens epithelial cells (HLECs), are the key issues for siRNA to complete the gene silencing in eyes. Previous studies have found that trimethyl chitosan (TMC) could cause biological adhesion under the corneal charged environment and interact with tight junction proteins to promote the distribution of particles in the deeper corneal epithelial cells by paracellular pathway. In order to further improve HLECs-targeting effect, in combination with the typical difference of distribution of adherens junction protein E-cadherin in epithelium of cornea and lens, from cell membrane to the cytoplasm, we design the construction of a PARP-1 siRNA-loaded asymmetric lipid bilayers nanoparticle with Ca-P as cores (siNPs) and achieve high encapsulation. TMC and TMC-ADT6 peptides copolymer work as outer layer-modifying materials to separately open corneal tight junction/adherens junction, target to cytoplasm of HLECs and achieve endosomal escape of PARP-1 siRNA. The siNPs are assumed to adjust the cell permeability, enhance the targeting effect and stability of siRNA and ultimately improve the ophthalmic application of PARP-1 siRNA in the treatment of cataract from the animal, tissue and cell levels. The work will provide a systematic and universal model to study transmembrane ocular absorption of water soluble and macromolecular drugs, and further enrich the ocular drug delivery system theory.