Immuno-engineered macrophage membrane-coated nanodrug to restore immune balance for rheumatoid arthritis treatment.

Current immunosuppressive therapies for rheumatoid arthritis (RA) lack disease specificity, primarily targeting inflammation while causing debilitating side effects. To address this limitation, we developed a biomimetic nanodrug MP@NEs/CT to induce antigen-specific immune tolerance for precise, effective and safe RA immunotherapy. MP@NEs/CT features a core of multiepitope citrullinated peptide (CitP) and triptolide (TPL) co-loaded nanoemulsion and coated with a macrophage membrane harvested from IFN-γ treated RAW264.7 cells. CitP, an RA autoantigen, specifically targets the immune response, while TPL acts as an immunosuppressant by inhibiting dendritic cells (DCs) maturation. IFN-γ treatment upregulates programmed death-ligand 1 (PD-L1) expression, facilitating MP@NEs/CT accumulation within inflamed tissues via programmed death-1 (PD-1) binding following intravenous administration. Additionally, the immune-engineered macrophage membrane sequesters proinflammatory cytokines, further dampening local inflammation. A significant reduction of CII-specific IgG levels in collagen-induced arthritis (CIA) mice model provides the evidence of CitP in restoring antigen-specific immune tolerance. Importantly, a low dose of TPL within MP@NEs/CT promotes tolerogenic DCs and generation of anti-inflammatory cytokines, ultimately leading to upregulation of antigen-specific regulatory T cells (Tregs) and B cells (Bregs) and a reduction in pro-inflammatory cytokine levels. Consequently, the nanodrug demonstrates synergistic and effective anti-inflammatory and immunosuppressive effects, alleviating autoimmune damage in a CIA mice model. STATEMENT OF SIGNIFICANCE: : Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by dysregulated immune responses, leading to synovial hyperplasia, tissue destruction, and irreversible disability. Early work in RA therapy mainly applying anti-inflammatory drugs which focuses on delaying joint deformity, but have no effects on the aberrant immune response. However, these drugs often require high doses and long-term administration, leading to potential adverse effects. In this work, we reported a therapeutic system that co-delivery of autoantigens with immune modulators promotes antigen-specific tolerance for effective and safe RA immunotherapy.