Shuai Xu,1– 5,* Yiyao Zeng,1,2,* Xin Tan,1,2 Ge Zhang,3– 5 Anchen Xu,1,2 Huimin Fan,6 Fengyi Yu,7 Zhen Qin,3– 5 Yahui Song,6 Yufeng Jiang,1,2 Xiangyu Wang,1,2 Duoduo Zhang,8 Yuxin Nong,1,2 Dede Lian,9 Junnan Tang,3– 5 Yafeng Zhou1,2 

1Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, People’s Republic of China; 2Institute for Hypertension, Soochow University, Suzhou, 215000, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Cardiology, Henan Province Key Laboratory of Cardiac Injury and Repair, Zhengzhou, 450052, People’s Republic of China; 5Department of Cardiology, Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, 450052, People’s Republic of China; 6Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital to Soochow University, Suzhou, 215028, People’s Republic of China; 7College of Veterinary Medicine, NC State University, Raleigh, NC, USA; 8Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China; 9Department of Intensive Care Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yafeng Zhou, Department of Cardiology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215000, People’s Republic of China, Email Dryafengzhou@163.com Junnan Tang, Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email fcctangjn@zzu.edu.cn

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.

Keywords: liposome, exosome-miR-185-5p inhibitor, dilated cardiomyopathy, apoptosis, cuproptosis