Monocyte/macrophage targeting drug delivery system (MTDS) has been highly focused as an emerging routine for delivering drugs to various macrophage related diseases. However, the distinguishing ability towards different macrophage related diseases of these systems and the impact of them on macrophage function and disease progression have not been systematically revealed, which is significantly important for active targeting therapeutic or diagnostic strategies. Herein, taking dextran modified polystyrene nanoparticles (DEX-PS) as example, we demonstrate that modification by dextran can specifically enhance the recognition of nanoparticles (NPs) by M2 macrophages in vitro, however, which is obstructed by monocytes in peripheral blood proved by in vivo assays. DEX-PS is not only targeted distributed in tumor, a M2 macrophage related disease, but also highly distributed in M1 macrophages related disease, acute peritonitis. Additionally, DEX-PS play a double-edged role in these two different diseases by reeducating macrophages to pro-inflammatory phenotype. These results suggest that MTDS, even those designed based on the different expression of receptor on different macrophages subtypes, lacks distinguishing ability for different macrophage subsets related diseases in vivo. In addition to the potential impact of these carrier materials on the function of macrophages, in the study of MTDS, great attention should be paid to the distribution of nanoparticles in non-target diseases and the impact on its disease process.