siRNA用于治疗克罗恩病（CD）的关键在于如何实现siRNA在肠道炎症组织的靶向、高效、安全递送。本研究设计了一种TNF-α siRNA的口服给药载体，用于解决siRNA靶向递送和抗炎治疗的几个关键问题：（1）利用可高效穿膜、打孔的α螺旋阳离子聚多肽实现siRNA在巨噬细胞的高效递送，解决巨噬细胞转染效率差的问题。（2）通过可逆交联聚多肽实现siRNA稳定包载、提高胃肠道稳定性；载体在胞内还原环境解交联，解决siRNA胞内释放的问题。（3）设计活性氧自由基（ROS）敏感的PEG修饰聚多肽纳米载体，用于区分正常小肠组织和炎症组织，实现炎症靶向siRNA递送，解决小肠吸收带来的全身基因沉默、免疫反应紊乱的问题。（4）设计酯酶敏感的聚多肽，其在胞内酯酶作用下从α螺旋向无规卷曲转变，解决材料转染后毒性的问题。本研究对于实现siRNA口服给药和CD局部靶向治疗具有重要意义。

Targeted, efficient, and safe delivery of siRNA into inflammatory tissues serves as a critical factor for the successful treatment of Crohn’s disease (CD) via RNA interference. In the current study, we aim to develop an oral delivery system for tumor necrosis factor α (TNF-α) siRNA to solve several critical challenges against inflammation-targeted oral RNAi. (1) We design helical polypeptide to mediate efficient siRNA delivery into macrophages to potentiate the transfection efficiency. (2) We reversibly crosslink the polypeptide to enhance siRNA encapsulation and stability in the GI tract; redox-responsive de-crosslinking allows on-demand siRNA release in the cytoplasm. (3) We covalently attach PEG onto the surface of nanocomplexes via ROS-cleavable thioketal linker to diminish intestinal absorption while potentiate targeted uptake in macrophages at the inflammation site. (4) We further design esterase-responsive polypeptide which undergoes diminishment of cationic charge density and helicity in the cytoplasm to reduce post-transfection material toxicity. This study thus provides a useful strategy for oral siRNA delivery and inflammation-targeted gene therapy for CD.