Xu Shuai, Zeng Yiyao, Tan Xin, Zhang Ge, Xu Anchen, Fan Huimin, Yu Fengyi, Qin Zhen, Song Yahui, Jiang Yufeng, Wang Xiangyu, Zhang Duoduo, Nong Yuxin, Lian Dede, Tang Junnan, Zhou Yafeng
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.
Institute for Hypertension, Soochow University, Suzhou, 215000, People's Republic of China.
Int J Nanomedicine. 2025 Jul 28;20:9407-9425. doi: 10.2147/IJN.S522157. eCollection 2025.
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.
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.
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.
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.
扩张型心肌病（DCM）是心力衰竭的一种常见形式，治疗选择有限。本研究探索了一种新的治疗策略，即递送包裹于脂质体中的外泌体来源的miRNA-185-5p抑制剂，旨在靶向心脏组织并减轻DCM中的心肌细胞凋亡和铜死亡。
在我们之前的研究中鉴定并从外泌体中提取的miRNA-185-5p抑制剂被包裹于用心脏靶向肽功能化的脂质体中。该系统用于阿霉素（DOX）诱导的DCM的体外和体内模型。我们使用超声心动图、组织学分析、蛋白质印迹和生化分析评估了这种治疗对心脏功能、细胞凋亡、铜死亡、氧化应激和纤维化的影响。
体外实验表明，Lipo@miR-185-5p抑制剂显著减轻了H9C2细胞和诱导多能干细胞衍生的心肌细胞中的细胞凋亡和铜死亡，凋亡细胞率降低了42.6%，铜死亡相关标志物下调了50%以上（均P<0.01）。在体内，靶向脂质体制剂显著改善了DOX诱导的DCM小鼠的心脏功能，左心室射血分数（LVEF）增加了27.3%，心肌纤维化面积减少了36.5%（P<0.01），同时提高了生存率。这些发现强调了这种靶向递送策略治疗扩张型心肌病的治疗潜力。
Lipo@miR-185-5p抑制剂利用外泌体来源的miRNA和靶向脂质体递送，有效减轻了DCM诱导的心肌功能障碍。这种方法通过靶向心力衰竭中涉及的特定分子机制，代表了一种有前景的心血管疾病治疗策略。
