The undesirable inflammation and the excessive M1 macrophage activity may lead to inflammatory diseases. Corticosteroids and stem cell therapy are used in clinical practice to promote anti-inflammatory responses. However, this protocol has limitations and is associated with numerous side effects. In this study, the synergistic anti-inflammatory effects of dexamethasone (Dex) and mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) were evaluated to enhance the polarization of M1 inflammatory macrophages into the anti-inflammatory (M2) phenotype. Hence, we designed different combinations of Dex and EVs using three methods, including EVs isolated from Dex-preconditioned MSCs (Pre-Dex-EVs), EVs loaded with Dex (L-Dex-EVs), and EVs and Dex co-administration (Dex + EVs). All designed EVs had a significant effect on reducing the expression of M1-related genes (iNOS, Stat1, and IRF5), cytokines (IL6 and TNF-a), and CD markers (CD86) in lipopolysaccharide-stimulated macrophages. On the other hand, these combinations promoted the expression of alternative-activated M2-related genes (Arg-1, Stat6, and IRF4), cytokine (IL10), and CD markers (CD206).

The combination of Dex and MSC-EVs enhances the effectiveness of both and synergistically promotes the conversion of inflammatory macrophages into an anti-inflammatory state.

不良炎症和过度的M1巨噬细胞活性可能导致炎症性疾病。皮质类固醇和干细胞疗法在临床实践中用于促进抗炎反应。然而，该方案有局限性并且与许多副作用相关。在这项研究中，评估了地塞米松 (Dex) 和间充质干细胞来源的细胞外囊泡 (MSC-EV) 的协同抗炎作用，以增强 M1 炎症巨噬细胞极化为抗炎 (M2) 表型。因此，我们使用三种方法设计了 Dex 和 EV 的不同组合，包括从 Dex 预处理的 MSC 中分离的 EV（Pre-Dex-EV）、加载 Dex 的 EV（L-Dex-EV）以及 EV 和 Dex 共同给药（ Dex + EV）。所有设计的 EV 对降低脂多糖刺激的巨噬细胞中 M1 相关基因（iNOS、Stat1 和 IRF5）、细胞因子（IL6 和 TNF-a）和 CD 标记物（CD86）的表达具有显着效果。另一方面，这些组合促进了替代激活的 M2 相关基因（Arg-1、Stat6 和 IRF4）、细胞因子（IL10）和 CD 标记物（CD206）的表达。

Dex和MSC-EV的组合增强了两者的有效性，并协同促进炎症巨噬细胞向抗炎状态的转化。