Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.
Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, 646000, China.
J Control Release. 2022 Jan;341:16-30. doi: 10.1016/j.jconrel.2021.11.019. Epub 2021 Nov 16.
Imbalance between the activities of pro-inflammatory M1 and anti-inflammatory M2 macrophages in rheumatoid arthritis (RA) induces synovial inflammation and autoimmunity, leading to joint damage. Here we encapsulated a plasmid DNA encoding the anti-inflammatory cytokine interleukin-10 (IL-10 pDNA) and the chemotherapeutic drug betamethasone sodium phosphate (BSP) into biomimetic vector M2 exosomes (M2 Exo) derived from M2-type macrophages. We demonstrate that the loaded exosomes target and reduce inflammation for combined therapy against RA. The in vitro efficiency of the M2 Exo/pDNA/BSP co-delivery system was attributed to the synergistic effect of IL-10 pDNA and BSP, which also promoted M1-to-M2 macrophage polarization by reducing the secretion of pro-inflammatory cytokines (IL-1β, TNF-α) and increasing the expression of IL-10 cytokine. In a mouse model of RA, M2 Exo/pDNA/BSP showed good accumulation at inflamed joint sites, high anti-inflammatory activity, and potent therapeutic effect. The delivery system was non-toxic both in vitro and in vivo. Thus, this system may serve as a promising biocompatible drug carrier and anti-inflammatory agent for RA treatment based on M1-to-M2 macrophage re-polarization.
在类风湿关节炎（RA）中，促炎 M1 型和抗炎 M2 型巨噬细胞的活性失衡会引发滑膜炎症和自身免疫反应，导致关节损伤。在这里，我们将编码抗炎细胞因子白细胞介素 10（IL-10 pDNA）和化疗药物倍他米松磷酸钠（BSP）的质粒 DNA 包裹在仿生载体 M2 型巨噬细胞衍生的小体（M2 Exo）中。我们证明了负载的外体可以靶向并减轻炎症，从而实现针对 RA 的联合治疗。M2 Exo/pDNA/BSP 共递药系统的体外效率归因于 IL-10 pDNA 和 BSP 的协同作用，这也通过减少促炎细胞因子（IL-1β、TNF-α）的分泌和增加 IL-10 细胞因子的表达促进了 M1 型向 M2 型巨噬细胞的极化。在 RA 小鼠模型中，M2 Exo/pDNA/BSP 在发炎关节部位有很好的聚集，具有高抗炎活性和强大的治疗效果。该递送系统在体外和体内均无毒性。因此，该系统可能成为一种有前途的基于 M1 型向 M2 型巨噬细胞再极化的 RA 治疗用生物相容性药物载体和抗炎剂。
