Rheumatoid arthritis (RA) is an autoimmune disease with unclear pathogenesis. Hydroxychloroquine (HCQ), despite its moderate anti-RA efficacy, is among the few clinical drugs used for RA therapy. Macrophages reportedly play a vital role in RA. Here, we designed and explored macrophage-targeted HCQ nanotherapeutics based on mannose-functionalized polymersomes (MP-HCQ) for RA therapy. Notably, MP-HCQ exhibited favorable properties of less than 50 nm size, glutathione-accelerated HCQ release, and M1 phenotype macrophage (M1M) targetability, leading to repolarization of macrophages to anti-inflammatory M2 phenotype (M2M), reduced secretion of pro-inflammatory cytokines (IL-6), and upregulation of anti-inflammatory cytokines (IL-10). The therapeutic studies in the zymosan-induced RA (ZIA) mouse model showed marked accumulation of MP-HCQ in the inflammation sites, ameliorated symptoms of RA joints, significantly reduced IL-6, TNF-α, and IL-1β, and increased IL-10 and TGF-β compared with free HCQ. The analyses of RA joints disclosed greatly amplified M2M and declined mature DCs, CD4+ T cells, and CD8+ T cells. In accordance, MP-HCQ significantly reduced the damage of RA joints, cartilages, and bones compared to free HCQ and non-targeted controls. Macrophage-targeted HCQ nanotherapeutics therefore appears as a highly potent treatment for RA.

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Inflammation targeted delivery of methotrexate using mannose-installed polymersomes (Man-PMTX) can repolarize macrophages from M1 type to M2 type and mitigate proinflammatory cytokines, leading to effectively augmented rheumatoid arthritis therapy.

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