Imbalance between the activities of pro-inflammatory M1 and anti-inflammatory M2 macrophages in rheumatoid arthritis (RA) induces synovial inflammation and autoimmunity, leading to joint damage. Here we encapsulated a plasmid DNA encoding the anti-inflammatory cytokine interleukin-10 (IL-10 pDNA) and the chemotherapeutic drug betamethasone sodium phosphate (BSP) into biomimetic vector M2 exosomes (M2 Exo) derived from M2-type macrophages. We demonstrate that the loaded exosomes target and reduce inflammation for combined therapy against RA. The in vitro efficiency of the M2 Exo/pDNA/BSP co-delivery system was attributed to the synergistic effect of IL-10 pDNA and BSP, which also promoted M1-to-M2 macrophage polarization by reducing the secretion of pro-inflammatory cytokines (IL-1β, TNF-α) and increasing the expression of IL-10 cytokine. In a mouse model of RA, M2 Exo/pDNA/BSP showed good accumulation at inflamed joint sites, high anti-inflammatory activity, and potent therapeutic effect. The delivery system was non-toxic both in vitro and in vivo. Thus, this system may serve as a promising biocompatible drug carrier and anti-inflammatory agent for RA treatment based on M1-to-M2 macrophage re-polarization. we engaged molecularly engineered M2 macrophage-derived exosomes with inflammation tropism and anti-inflammatory capabilities for co-delivery of IL-10 pDNA and GCs to achieve RA treatment via M1-to-M2 macrophages re-polarization. Display omitted •M2-type macrophage derived exosomes serve as simple endogenous drug carrier with inflammation targeting and anti-inflammatory properties.•The biomimetic co-delivery system attenuated inflammation in joint lesions and promoted M1-to-M2 macrophage polarization through the synergistic effect.•The biomimetic co-delivery system reduced the dose of glucocorticoid and its adverse effects.