安全高效的递送载体是制约核酸药物临床应用的重要因素。本项目围绕核酸药物递送载体的安全递送、高效释药和结构可控等关键科学问题，拟采用微流控技术精准组装具有酸敏反转结构特征的新型杂化纳米粒。以PCL-PEI分别与PHis-PEI和C18-Cp-PEI组成混合骨架材料，构建以PEI/siRNA复合物为核心、疏水片段（PCL和PHis或C18）堆积形成中间壳层、最外层覆盖中性脂膜的杂化纳米粒。研究比较两种不同促载体解散方式对siRNA药物释放的影响：在pH<6的介质条件下聚组氨酸（PHis）片段的酸敏荷正电相互排斥与磷酰胺键（Cp）的酸敏断裂引起材料解散。优选制剂包载EGFR-siRNA，以原位移植乳腺癌裸鼠为模型，进一步验证考察杂化纳米粒的体内安全性和抗肿瘤效应。本项目顺利实施将为探索和阐明新型杂化纳米粒的组装和释药机制，为解决递送siRNA的阳离子载体安全性和稳定性问题提供重要参考。

Safe and efficient carrier is the crucial limitation for clinical application of nucleic acid drugs. In this project, in order to obtain a stable, safe, efficient and controllable nucleic acid drug delivery system, we intend to use PCL-PEI and pH-sensitive PHis-PEI or C18-Cp-PEI to construct a novel supramolecular hybrid nanoparticle with microfluidic technology, in which the PEI/siRNA complex as the core, hydrophobic fragment (PCL and PHis or C18) as middle shell and the neutral lipid membranes as the outer coating. Under pH<6 medium, a different siRNA release will depended on different disassembly mechanisms of hybrid nanoparticle, which induced by pH-sensitive charge reversal of poly histidine (PHis) fragment and pH-sensitive cyclophosphamide cleavage of C18-Cp-PEI. The optimized EGFR-siRNA contained hybrid nanoparticles were be carried out in nude mice bearing tumor for further verifying in vivo safety and antitumor effects. In this study, we will discuss the assembly mechanism and the key factors that affect the biological effects of novel hybrid nanoparticles, and provide an important reference for developing a safe and efficient siRNA delivery system.