Therapeutic potential of extracellular vesicle-mediated miRNA delivery based on liver-heart crosstalk for cardiac injury

Background/Introduction Extracellular vesicles (EV) have gained attention as promising nanocarriers for miRNA delivery in vivo. However, their clinical application is limited by predominant accumulation in the liver after systemic administration. Interestingly, recent studies have shown the importance of inter-tissue crosstalk mediated by endocrine factors, including secreted proteins, in maintaining physiological homeostasis. Although the liver and heart engage in multifaceted interactions, few studies have explored the potential of liver-heart crosstalk in the development of nanomedicine through EV-based miRNA delivery. Purpose This study aimed to explore the therapeutic potential of liver-heart crosstalk in cardiac injury by strategically leveraging the predominant liver accumulation, a great challenge in EV-based miRNA delivery. Methods To investigate molecular changes in the liver during cardiac injury, RNA-sequencing analysis was performed on the liver of angiotensin II (Ang II)-treated mice. EV were isolated from mesenchymal stem cells (MSC) and characterized using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Then, miRNA-155, a well-known master regulator of inflammation, was loaded into MSC-derived EV (EV@miR-155). The cardioprotective effects of EV@miR-155 mediated by liver-heart crosstalk were evaluated in Ang II-treated mice. Results After RNA-sequencing analysis, we identified 2,218 differentially expressed genes in the liver of Ang II-treated mice compared to untreated controls, including 1,915 upregulated and 303 downregulated genes (|fold change| ≥ 2, P < 0.05). Notably, these genes were involved in multiple pathophysiological mechanisms of cardiac injury, including regulation of inflammatory response. To achieve liver-heart crosstalk-mediated treatment for cardiac injury, we prepared EV@miR-155 by loading miRNA-155 into MSC-derived EV. We then confirmed that EV@miR-155 exhibited typical round, cup-shaped particles with diameters of ~150 nm. In Ang II-treated mice, intravenous injection of EV@miR-155 primarily accumulated in the liver (P < 0.05) and significantly increased hepatic miRNA-155 expression. Consequently, EV@miR-155 significantly improved cardiac function and reduced myocardial fibrosis, cardiomyocyte cross-sectional area, and inflammatory response (P < 0.05) without inducing systemic toxicity. Mechanistically, we found liver-heart crosstalk-mediated regulation of inflammatory response, in which upregulation of miRNA-155 in the liver activated the inflammatory IL-6/STAT3 pathway, promoted the production of cardioprotective hepatokines, and ultimately exerted cardioprotective effects. Conclusion Our findings suggest a new perspective on EV-based miRNA delivery through liver-heart crosstalk, thereby providing a novel strategy for treating cardiac injury.