Combination therapy is an emerging approach for treating ulcerative colitis (UC). During the development of UC, TNF-α acts as the major pro-inflammatory cytokine while interleukin-22 (IL-22) plays an important role in preventing mucosal damage. In the present study, we loaded TNF-α siRNA (siTNF) into galactosylated polymeric nanoparticles (NPs). The resultant Gal-siTNF-NPs had a desirable diameter (～261 nm), narrow size distribution and a slightly negative zeta potential (～‒12 mV). These NPs successful mediated the targeted delivery of siTNF to macrophages and efficiently inhibited the expression of TNF-α.