肝细胞癌发病率在世界最常见的肿瘤中排名第六，死亡率居第三位。中晚期肝癌患者主要依赖化疗，顺铂是最常用传统化疗药物之一，但其耐药性问题突出。NOR1是项目申请者克隆并命名的基因，属于有机溶质载体家族，具有介导药物清除的功能。前期研究发现NOR1在肝细胞癌中呈中高度表达，通过抑制MAPK信号通路介导顺铂耐药。本项目构建了红细胞膜伪装的银金属有机框架（Ag-MOFs），同时负载顺铂及NOR1 shRNA的双靶向纳米药物载体系统，用于肝细胞癌顺铂耐药的逆转效应研究。该系统具有良好的生物相容性，可利用顺铂释放后Ag-MOFs荧光恢复实时监测顺铂释放情况。本研究通过探讨NOR1在肝细胞癌清除顺铂过程中的作用及对蛋白激酶通路中RAS/RAF/MAPK/c-JUN等分子的影响，阐明纳米药物载体系统逆转顺铂耐药增强抗肝癌作用的机制，为治疗肝细胞癌提供新的耐药靶点及安全有效的基因治疗策略。

Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death in the world. Patients with advanced liver cancer patients mainly rely on chemotherapy. Cisplatin is one of the most commonly used traditional chemotherapy drugs and its drug resistance problem is prominent. NOR1, a gene cloned and named by the project applicant, belongs to organic solute carriers family and mediates drug clearance. Previous studies revealed that NOR1 was highly expressed in hepatocellular carcinoma and leading to cisplatin resistance by inhibiting MAPK pathway. In this study, an erythrocyte membrane camouflage Ag-MOFs (Ag-MOFs) coupled with cisplatin and NOR1 shRNA was constructed, this dual targeting nanocarrier system is used for collaborative treatment of hepatocellular carcinoma. The system has good biocompatibility, and Ag-MOFs fluorescence recovery after cisplatin release can be used to monitor cisplatin release in real time. The role of NOR1 in cisplatin clearance by hepatocellular carcinoma and the effect of NOR1 on RAS/RAF/MAPK/c-Jun in protein kinase pathway, were explore to elucidate the mechanism of reversal of cisplatin resistance and enhanced anti-tumor effect by nano-drug delivery system, which provided new drug resistance targets and effective gene therapy strategies for the treatment of hepatocarcinoma.