Rheumatoid arthritis (RA) is a chronic, progressive, and inflammatory systemic autoimmune disease. Effective drug therapy for RA is hindered by severe side effects due to inefficient delivery to the disease site and broad drug distribution. Inspired by biomimetic biology, this study developed a drug delivery system of adipose-derived mesenchymal stem cell membrane-encapsulated nanoparticles for the treatment of RA. The intact adipose-derived mesenchymal stem cell (ADSC) membrane was coated on poly (lactic-co-glycolic acid) (PLGA) nanoparticles and loaded with tacrolimus (FK506), a T cell inhibitor. The ADSC membrane encapsulated on nanoparticles retains the original homing properties of ADSC, targeting the inflamed joints and enhancing tacrolimus anti-inflammatory effect. Both in vitro and in vivo experiments proved that the synergistic effect of the ADSC-membrane and tacrolimus effectively inhibited inflammation in vivo and reduced the expression of pro-inflammatory factors (IL-1β, IL-6, tumor necrosis factor-α (TNF-α)), and increased the expression of anti-inflammatory factors (IL-10). In addition, collagen-induced arthritis (CIA) model results also showed that the drug delivery system could effectively reduce the destruction of articular cartilage and bone in mice without causing any adverse effects. This study provided a new biomimetic targeting strategy to reshape the inflammatory microenvironment by modulating T cell subsets, providing new inspiration for RA treatment.