State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin, 300350, China.
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, 266071, China.
Adv Healthc Mater. 2023 Nov;12(29):e2301325. doi: 10.1002/adhm.202301325. Epub 2023 Aug 11.
Overactivated macrophages are a prominent feature of many inflammatory and autoimmune diseases, including sepsis. Attention and regulation of macrophages activity is of great significance for sepsis treatment. Herein, this study shows that folic acid-functionalized exosomes accumulate in the lung of septic mice and specifically target inflammatory macrophages. Therefore, FA-functionalized exosomes co-loaded with resveratrol (an anti-inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA-Exo/R+C), which exhibit powerful anti-inflammatory and immunosuppressive activities against LPS-stimulated macrophages in vitro by regulating NF-κB and ERK1/2 signaling pathways, are designed. Encouraged by these positive data, the efficacy of FA-Exo/R+C is systematically investigated in an LPS-induced mouse sepsis model. FA-Exo/R+C shows striking therapeutic benefits in terms of attenuated cytokine storm, reduced acute lung injury, and increased survival of septic mice by inhibiting the inflammation and proliferation of proinflammatory M1 macrophages. Importantly, multiple administrations of FA-Exo/R+C significantly enhance and prolong the protective effect, and resist rechallenge to LPS. Collectively, the strategy of co-delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment.
过度激活的巨噬细胞是许多炎症和自身免疫性疾病的一个显著特征，包括脓毒症。关注和调节巨噬细胞的活性对脓毒症的治疗具有重要意义。本研究表明，叶酸功能化的外泌体在脓毒症小鼠的肺部积聚，并特异性靶向炎症性巨噬细胞。因此，设计了负载有白藜芦醇（一种抗炎多酚）和雷公藤红素（一种免疫抑制的五环三萜；FA-Exo/R+C）的 FA 功能化外泌体，它们通过调节 NF-κB 和 ERK1/2 信号通路，在体外对 LPS 刺激的巨噬细胞表现出强大的抗炎和免疫抑制作用。受这些积极数据的鼓舞，我们在 LPS 诱导的脓毒症小鼠模型中系统地研究了 FA-Exo/R+C 的疗效。FA-Exo/R+C 通过抑制促炎 M1 巨噬细胞的炎症和增殖，在减轻细胞因子风暴、降低急性肺损伤和提高脓毒症小鼠存活率方面表现出显著的治疗益处。重要的是，多次给予 FA-Exo/R+C 可显著增强和延长保护作用，并抵抗 LPS 的再挑战。总之，通过功能化外泌体共递送药物组合的策略为脓毒症的治疗提供了新的途径。
