In this work, a novel nanoparticle (NP)-based formulation (i.e., nanomedicine) was developed to specifically deliver coenzyme Q10 (CoQ10) to macrophages for treating rheumatoid arthritis (RA). The NPs containing the matrix metalloproteinase (MMP)-responsive polymer, polyethylene glycol-peptide-phosphatidylethanolamine (PEG-pp-PE), and phosphatidylserine were designed, in which the NPs' PEG "corona" decreased nonspecific interaction, and the overexpressed MMP-2/9 in the inflamed synovium triggered PEG deshielding and PS-mediated phagocytosis. The NPs were prepared by a thin-film hydration method, and their particle size, zeta potential, drug loading, and drug release were determined. CoQ10 could be loaded into the NPs with a drug loading of about 9.7% at the polymer/PS ratio of 50:50. The CoQ10-loaded NPs had a particle size of <200 nm and a zeta potential of ∼-40 mV and showed sustained drug release under simulated sink conditions at 37 °C. In the presence of MMPs, the NPs were efficiently taken up by macrophages (RAW264.7 cells) with cellular uptake 3.5-fold higher than that of the NPs in the absence of MMPs. More significantly, the NPs' uptake in RAW264.7 cells was >13-fold higher than that in fibroblasts (NIH3T3 cells) in the presence of MMPs, whereas this difference was ∼2-fold in the absence of MMPs, indicating the NPs' MMP-sensitive macrophage selectivity. In the LPS- and IFN-γ-stimulated macrophages or cell cocultures, the CoQ10-loaded NPs significantly inhibited the production of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while enhancing the production of the anti-inflammatory cytokine (IL-10) in response to MMP pretreatment. The CoQ10-loaded NPs also significantly inhibited macrophage activation, as evidenced by changes in cell morphology and alterations in macrophage activation-related markers, including CD80, CD86, MHCII, and CD206. The CoQ10-loaded NPs did not show significant cytotoxicity in the tested cells. Our results suggest that the developed MMP-sensitive macrophage-targeted NPs might work as a "smart" nanomedicine for RA treatments.