肝癌中miR-34a表达偏低或缺失，miR-34a替代疗法可恢复其水平，负性调节肝癌的增殖及转移。传统替代疗法因缺乏靶向性导致正常细胞受累，“脱靶”副反应严重。本研究基于富含环糊精的聚阳离子材料，通过自组装技术修饰功能客体并引入二硫键，构成具有氧化还原敏感性（R）、肝癌靶向性（O）、主客体自组装（S）、高效转染（E）的ROSE多功能基因药物输送体系。研究拟用ROSE系统携带miR-34a给药，通过靶向输送、控制释放，定点高效地作用肝癌组织。将以LM3肝癌细胞为对象，对其持续稳定地功能性表达miR-34a治疗基因，评价靶向肝癌的特异性、治疗效果及机制；已构建荷瘤裸鼠模型，将进行靶向性、药代动力学和体内疗效的研究。ROSE系统将增加miR-34a疗法靶向性，降低“脱靶”所致的副作用，提高药物生物利用度，实现多功能性基因运载，解决基因疗法给药难题，为开发新的肝癌防治手段提供有力的基础和实践依据。

Attenuation or loss of miR-34a expression occurs in hepatocellular carcinoma (HCC). miR-34a replacement therapy restores miR-34a level and negatively modulates proliferation and metastasis of HCC. Conventional miR-34a therapy has tumor specificity, leading to severe “off-target” effect in normal cells. In this study, cyclodextrin-based polycations self-assemble with the functional moieties via host-guest interaction, forming a Redox-sensitive (R), Oligopeptide-guided (O), Self-assembly (S), and Efficiency-enhanced (E) multifunctional delivery system (ROSE). ROSE-mediated miR-34a therapy features targeted delivery and controlled release, resulting in efficient miR-34a expression specifically in HCC. We will study the stable and functional miR-34a delivery to LM3 HCC cells, and evaluate its tumor specificity, therapeutic effect, and underlying mechanisms. We will also study the in vivo tumor specificity, pharmacodynamics, and treatment applications in an established tumor-bearing nude mice model. ROSE system will gain targeting ability in miR-34a therapy, reduce “off-target” adverse effect, and increase drug bioavialability, which will achieve a multifunctional gene delivery. ROSE-mediated miR-34a therapy would solve the dilemma in gene therapy, and provide novel strategies for HCC treatment.