Yang Jiaxin, Yun Xinyi, Zheng Weihan, Zhang Huihui, Yan Zi, Chen Youyu, Xue Wanting, Mi Siqi, Li Ziyue, Sun Hanxiao, Xiao Guozhi, Dai Zhenning, Li Shiyu, Huang Wenhua
Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Digital Medicine and Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Department of Cell Biology, School of Basic Medical Science, Southern Medical University, 510515, Guangzhou, China.
J Nanobiotechnology. 2025 Jun 13;23(1):439. doi: 10.1186/s12951-025-03474-z.
Acute myocardial infarction remains a leading cause of mortality, with ischemia-reperfusion (I/R) injury causing severe myocardial damage through mitochondrial dysfunction. While mesenchymal stem cell-derived exosomes (MSC-Exo) show therapeutic potential, their limited targeting and insufficient mitochondrial protection restrict clinical application.
We developed a novel engineered exosome platform (Exo-I-S) using an IRES-driven bicistronic plasmid to co-load Sirtuin3 (SIRT3) and GPI-Insulin, aiming to enhance targeting efficiency and mitochondrial protection. The platform was evaluated in both in vitro and in vivo models of myocardial I/R injury. In vitro, Exo-I-S achieved faster cellular uptake, improved mitochondrial function, and reduced oxidative stress in H9c2 cells. The platform activated PI3K/AKT signaling, enhanced Glut4 translocation, and improved mitochondrial respiratory capacity. In a rat I/R injury model, Exo-I-S significantly reduced infarction size, improved cardiac function, and enhanced glucose metabolism, with superior therapeutic outcomes compared to unmodified exosomes.
The dual functionality of Exo-I-S, combining insulin-mediated targeting with SIRT3-driven mitochondrial protection, provides a promising strategy for I/R injury treatment. Future studies should focus on optimizing targeting specificity and developing sustained release mechanisms to enhance clinical applicability.
急性心肌梗死仍然是主要的死亡原因，缺血再灌注（I/R）损伤通过线粒体功能障碍导致严重的心肌损伤。虽然间充质干细胞衍生的外泌体（MSC-Exo）显示出治疗潜力，但其有限的靶向性和不足的线粒体保护作用限制了其临床应用。
我们使用内部核糖体进入位点（IRES）驱动的双顺反子质粒开发了一种新型工程化外泌体平台（Exo-I-S），用于共负载沉默调节蛋白3（SIRT3）和糖基化磷脂酰肌醇锚定胰岛素（GPI-胰岛素），旨在提高靶向效率和线粒体保护作用。该平台在心肌I/R损伤的体外和体内模型中均进行了评估。在体外，Exo-I-S在H9c2细胞中实现了更快的细胞摄取、改善了线粒体功能并降低了氧化应激。该平台激活了PI3K/AKT信号通路，增强了葡萄糖转运蛋白4（Glut4）的转位，并改善了线粒体呼吸能力。在大鼠I/R损伤模型中，Exo-I-S显著减小了梗死面积，改善了心脏功能，并增强了葡萄糖代谢，与未修饰的外泌体相比具有更好的治疗效果。
Exo-I-S的双重功能，即将胰岛素介导的靶向作用与SIRT3驱动的线粒体保护作用相结合，为I/R损伤治疗提供了一种有前景的策略。未来的研究应集中在优化靶向特异性和开发缓释机制以提高临床适用性。
