Acta Biomater. 2025 Mar 15:S1742-7061(25)00197-7. doi: 10.1016/j.actbio.2025.03.023. Online ahead of print.
ABSTRACT
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.
PMID:40097125 | DOI:10.1016/j.actbio.2025.03.023