Engineering Efferocytosis-Mimicking Nanovesicles to Regulate Joint Anti-Inflammation and Peripheral Immunosuppression for Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial joints and the dysfunction of regulatory T cells (Tregs) in the peripheral blood. Therefore, an optimal treatment strategy should aim to eliminate the inflammatory response in the joints and simultaneously restore the immune tolerance of Tregs in peripheral blood. Accordingly, we developed an efferocytosis-mimicking nanovesicle that contains three functional factors for immunomodulating of efferocytosis, including "find me" and "eat me" signals for professional (macrophage) or non-professional phagocytes (T lymphocyte), and "apoptotic metabolite" for metabolite digestion. We showed that efferocytosis-mimicking nanovesicles targeted the inflamed joints and spleen of mice with collagen-induced arthritis, further recruiting and selectively binding to macrophages and T lymphocytes to induce M2 macrophage polarization and Treg differentiation and T helper cell 17 (Th17) recession. Under systemic administration, the efferocytosis-mimicking nanovesicles effectively maintained the pro-inflammatory M1/anti-inflammatory M2 macrophage balance in joints and the Treg/Th17 imbalance in peripheral blood to prevent RA progression. This study demonstrates the potential of efferocytosis-mimicking nanovesicles for RA immunotherapy. We designed and prepared efferocytosis-mimicking nanovesicles, that can effectively target inflamed joints, induce anti-inflammatory M2 macrophages, and accumulate in the spleen to regulate the imbalance between Treg and Th17 cells, thereby promoting peripheral immunosuppression and suppressing RA progression. image