Rheumatoid arthritis (RA) is a chronic autoimmune disease that gravely jeopardizes the quality of life of numerous people. Methotrexate (MTX) is a disease-modifying anti-rheumatic drug commonly used in clinics; however, it suffers from slow onset, moderate efficacy, and adverse reactions such as renal dysfunction, myelosuppression, and bone erosion after long-term treatment. Here, we explored macrophage targeted delivery of MTX using mannose-installed chimaeric polymersomes (Man-PMTX) as an advanced treatment for RA. Man-PMTX exhibited high (∼18 wt%) and robust loading of MTX, uniform size of 51-55 nm, minimal hemolytic activity, and glutathione-actuated drug release property. Man-PMTX showed better uptake by activated macrophages than PMTX, and more repolarization of bone marrow-derived macrophages (BMDMs) to anti-inflammatory M2 type macrophages and less secretion of TNF-α and IL-1β compared with free MTX and PMTX. In vivo studies revealed that Man-PMTX showed significantly higher accumulation in inflammatory joints than in healthy joints and effectively treated RA by relieving inflammation, repolarizing macrophages from M1 type to M2 type, and mitigating proinflammatory cytokines. Accordingly, Man-PMTX effectively protected the synovium and bone from damage. Mannose-mediated nanodelivery of methotrexate to macrophages appears to be an attractive strategy to augment rheumatoid arthritis therapy.