Targeted Delivery of Exosome-Derived miRNA-185-5p Inhibitor via Liposomes Alleviates Apoptosis and Cuproptosis in Dilated Cardiomyopathy.

Purpose: Dilated cardiomyopathy (DCM) is a prevalent form of heart failure with limited therapeutic options. This study explores a novel treatment strategy involving the delivery of exosome-derived miRNA-185-5p inhibitors encapsulated in liposomes, aiming to target cardiac tissue and alleviate myocardial apoptosis and cuproptosis in DCM. Methods: The miRNA-185-5p inhibitor, identified in our previous study and extracted from exosomes, was encapsulated in liposomes functionalized with a cardiac-targeting peptide. This system was used in both in vitro and in vivo models of DCM induced by doxorubicin (DOX). We evaluated the effects of this treatment on cardiac function, apoptosis, cuproptosis, oxidative stress, and fibrosis using echocardiography, histological analysis, Western blotting, and biochemical assays. Results: In vitro experiments demonstrated that the Lipo@miR-185-5p inhibitor markedly attenuated apoptosis and cuproptosis in H9C2 cells and iPSC-derived cardiomyocytes, with a 42.6% reduction in apoptotic cell rates and over 50% downregulation of cuproptosis-related markers (both P < 0.01). In vivo, the targeted liposomal formulation significantly improved cardiac function in DOX-induced DCM mice, as evidenced by a 27.3% increase in left ventricular ejection fraction (LVEF) and a 36.5% reduction in myocardial fibrosis area (P < 0.01), along with enhanced survival. These findings underscore the therapeutic potential of this targeted delivery strategy for the treatment of dilated cardiomyopathy. Conclusion: Lipo@miR-185-5p inhibitor, utilizing exosome-derived miRNA and targeted liposomal delivery, effectively alleviates DCM-induced myocardial dysfunction. This approach represents a promising therapeutic strategy for cardiovascular diseases by targeting specific molecular mechanisms involved in heart failure.