Dong Jiankai, Li Zechuan, Fu Chenxing, Yang Ding, Yang Huijie, Lin Li, Liang Xing-Jie, Chen Zhaoyang, Chen Lianglong, Guo Weisheng
Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 250001, China.
Department of Minimally Invasive Interventional Radiology, The Second Affiliated Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou 510260, China.
J Control Release. 2025 Jul 10;383:113799. doi: 10.1016/j.jconrel.2025.113799. Epub 2025 May 3.
Monocyte/macrophage (Mo/Mϕ) infiltration is critical in myocardial ischemia-reperfusion injury (MIRI). However, the complex composition of the myocardium severely hinders drug accumulation and makes it challenging to modulate the Mo/Mϕ immune response at the MIRI site. The spleen, acting as a Mo/Mϕ reservoir, plays a crucial role in the development of MIRI along the cardiosplenic axis. Compared to directly delivering medications to the MIRI site, targeting the spleen for Mo/Mϕ immunomodulation provides an alternative strategy to modulate the immunological phenotype on-site. Therefore, we developed a melatonin-loaded liposome (ST-MT@lipo2) that specifically targets the spleen and can effectively regulate the immunological response of splenic monocytes and macrophages, consequently enhancing their immune response at the site of MIRI. Additionally, the splenectomy mouse model revealed that ST-MT@lipo2 regulated MIRI's immune response through the cardiosplenic axis by regulating the MCP-1/CCR2 pathway to reduce circulating inflammatory monocyte migration from the spleen to the MIRI site. Moreover, pathological staining and echocardiography showed that ST-MT@lipo2 reduced myocardial damage and improved cardiac function in MIRI mice. This study demonstrates the crucial importance of modulating the immune response in the cardiosplenic axis for treating MIRI, which also inspired the treatments for inflammatory diseases by controlling the spleen immunological milieu.
单核细胞/巨噬细胞（Mo/Mϕ）浸润在心肌缺血再灌注损伤（MIRI）中至关重要。然而，心肌复杂的组成严重阻碍了药物蓄积，使得在MIRI部位调节Mo/Mϕ免疫反应具有挑战性。脾脏作为Mo/Mϕ的储存库，在沿心脾轴的MIRI发展过程中起着关键作用。与直接将药物输送到MIRI部位相比，靶向脾脏进行Mo/Mϕ免疫调节提供了一种在局部调节免疫表型的替代策略。因此，我们开发了一种特异性靶向脾脏的载褪黑素脂质体（ST-MT@lipo2），它可以有效调节脾脏单核细胞和巨噬细胞的免疫反应，从而增强它们在MIRI部位的免疫反应。此外，脾切除小鼠模型显示，ST-MT@lipo2通过调节MCP-1/CCR2途径，减少循环炎症单核细胞从脾脏向MIRI部位的迁移，从而通过心脾轴调节MIRI的免疫反应。而且，病理染色和超声心动图显示，ST-MT@lipo2可减轻MIRI小鼠的心肌损伤并改善心脏功能。本研究证明了调节心脾轴免疫反应对治疗MIRI的至关重要性，这也为通过控制脾脏免疫环境来治疗炎症性疾病提供了思路。
