Today, increasing evidences of systemic side effects with the treatments available for IBD limit their therapeutic outcomes. The challenge is to target anti-TNF-α agent to the inflamed tissue. Here, we have demonstrated that TNF-α siRNA can be efficiently loaded into F4-80 antibody (Ab) coated PLA-PEG-Mal nanoparticles (NPs) to target colonic macrophages (MPs). The NPs were characterized for particle size, cytotoxicity, binding characteristics, etc. These NPs are ~600 nm in diameter, non-cytotoxic, and are efficiently taken up by MPs inhibiting TNF-α secretion by the MPs in vitro. In vivo, the release of TNFa siRNA loaded inside F4/80 Ab coated NPs into colitis mice model showed higher colitis attenuation (like reduced weight loss, MPO activity and neutrophils infiltration) when compared to NPs not covered. Thus, we have formulated an efficient targeted drug delivery system in which TNF-α-siRNA NPs coated with F4/80 Ab represent an efficient therapeutic option for diseases such as IBD.