发展高效的纳米载体对于提高siRNA的递送效率，实现RNA干扰技术在癌症和遗传性疾病治疗方面的应用具有关键作用。目前，siRNA递送研究主要集中在载体化学结构的优化及载体-siRNA纳米粒子表观物理化学性质对递送效率的影响，对纳米粒子内部结构的认识不足制约了siRNA纳米药物的发展。本项目拟利用活性自由基聚合及相关化学修饰，制备化学结构和分子量精确可控的高分子载体。利用中国散裂中子源的小角中子散射和常规测试手段，研究高分子-siRNA纳米粒子的结构，特别是内部结构（如微结构的尺寸和分布）与高分子载体结构、pH值、离子强度、高分子/siRNA比例以及siRNA递送效率的关系。本项目从内部结构这一新的角度，揭示siRNA纳米药物的构-效关系。项目实施将深化我们对高分子-siRNA纳米粒子结构及siRNA递送机理的认识，为设计新的siRNA载体，推进RNA干扰技术的临床应用提供发展思路和依据。

The development of efficient nanocarriers plays key role in the improvement of siRNA delivery and clinical application of the emerging RNA interference (RNAi) technology in the treatment of cancer and heritable diseases. Current studies on siRNA delivery focus on the structural optimization of delivery vehicles as well as effects of apparent physicochemical properties (e.g. size and surface charge) of carrier-siRNA nanoparticles (NPs) on the delivery efficacy. The lack of understanding of the internal structure of siRNA NPs substantially impends the development of siRNA nanodrugs. In this project, we will prepare copolymers with fine-tuned chemical structures and molecular weights for siRNA delivery using the living polymerization and post-polymerization modifications. Investigations on the structures of polymer-siRNA NPs, with focuses on the internal structures of NPs (e.g. the size and distribution of subunits), will be carried out using conventional physicochemical technologies and small angle neutron scattering (SANS) at the China Spallation Neutron Source (CSNS) to reveal their relationship with the structure of polymer carriers (composition and molecular weight), pH, ionic strength, the ratio of polymer and siRNA, as well as the efficacy of siRNA delivery. This study brings new thoughts to the structure-activity relationship of siRNA NPs in terms of the internal structure of NPs. The implementation of this project will provide more in-depth understanding on the mechanism of siRNA delivery. It will be also helpful for developing new types of siRNA delivery carriers and the advancement of RNAi-based therapeutics.