Harnessing liver-heart crosstalk via extracellular vesicle-mediated hepatic delivery of microRNAs for cardiac repair.

Extracellular vesicles (EVs) hold great potential to deliver microRNAs (miRNAs) in vivo; however, its preferential hepatic accumulation after systemic administration hinders the therapeutic efficacy of miRNAs. Inter-organ communication via endocrine factors is crucial for maintaining physiological homeostasis. Herein, the present study leveraged liver-heart crosstalk to overcome the hepatic tropism of EVs and reframe it as a therapeutic advantage for cardiac injury. In a mouse model of angiotensin II (Ang II)-induced cardiac injury, liver tissues showed distinct changes in inflammation-related proteins compared with saline-treated controls, indicating hepatic involvement in cardiac injury. To establish a liver-heart crosstalk-based therapeutic approach, EV@miR-155 were prepared by loading miRNA-155 into mesenchymal stem cell-derived EVs. After intravenous administration, EV@miR-155 predominantly accumulated in the liver, increased hepatic miRNA-155 levels, and remodeled the hepatic microenvironment. This remodeling suppressed PPARα-mediated production of fibroblast growth factor 21, a hepatokine implicated in cardiac pathophysiology, thereby establishing a liver-heart crosstalk axis. Remarkably, EV@miR-155 treatment significantly improved cardiac function and reduced myocardial fibrosis and hypertrophy without inducing systemic toxicity (P<0.05). Therefore, the present study provides a conceptual shift by transforming the natural hepatic tropism of EVs-traditionally regarded as a delivery limitation-into a therapeutic route that enables liver-heart crosstalk-mediated cardiac repair.