Cardiosplenic axis-targeted immunomodulatory liposome for myocardial ischemia-reperfusion injury treatment.

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.