Objective: To explore the possible utilization of chitosan/siRNA in the inflammatory bowel disease. Methods: The chitosan molecules were mixed with siRNA directly at the N/P ratio of 60 to formulate the chitosan/siRNA nanoparticles (NPs). The hydro diameter was measured by Zetasizer while the morphology and structure were observed by scanning electron microscope (SEM) and transmission electron microscope (TEM) respectively. The NPs were incubated with RNA enzyme followed separation in PAA and analyzed by 2% agarose electrophoresis. The LPS (10 μg/mL) was used to induce murine macrophages for 24 h and the NPs transfection was performed. The fluorescence microscope (FM) was used to observe the transfection efficiency. After transfection of siRNA targeting TNFα, the TaqMan RT-PCR and ELISA kit were used to measure the TNFα expression. In the meanwhile, the cells viability was assessed by MTT assay. Results: The NPs were homogeneous with the average size of 200 nm. It bonded with siRNA reversibly and could protect siRNA from enzyme degradation for more than 120 minutes. A high transfection efficiency was obtained in macrophages and TNFα expression was down regulated to more than 50% both in the mRNA level and protein level without apparent cytotoxicity. Conclusion: The chitosan/siRNA NPs can effectively transfect macrophages to suppress the TNFα expression, which may provide new insight into inflammatory bowel disease molecule therapy.