Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Republic of Korea.
J Extracell Vesicles. 2023 Oct;12(10):e12371. doi: 10.1002/jev2.12371.
Small-interfering RNA (siRNA) therapy is considered a powerful therapeutic strategy for treating cardiac hypertrophy, an important risk factor for subsequent cardiac morbidity and mortality. However, the lack of safe and efficient in vivo delivery of siRNAs is a major challenge for broadening its clinical applications. Small extracellular vesicles (sEVs) are a promising delivery system for siRNAs but have limited cell/tissue-specific targeting ability. In this study, a new generation of heart-targeting sEVs (CEVs) has been developed by conjugating cardiac-targeting peptide (CTP) to human peripheral blood-derived sEVs (PB-EVs), using a simple, rapid and scalable method based on bio-orthogonal copper-free click chemistry. The experimental results show that CEVs have typical sEVs properties and excellent heart-targeting ability. Furthermore, to treat cardiac hypertrophy, CEVs are loaded with NADPH Oxidase 4 (NOX4) siRNA (siNOX4). Consequently, CEVs@siNOX4 treatment enhances the in vitro anti-hypertrophic effects by CEVs with siRNA protection and heart-targeting ability. In addition, the intravenous injection of CEVs@siNOX4 into angiotensin II (Ang II)-treated mice significantly improves cardiac function and reduces fibrosis and cardiomyocyte cross-sectional area, with limited side effects. In conclusion, the utilization of CEVs represents an efficient strategy for heart-targeted delivery of therapeutic siRNAs and holds great promise for the treatment of cardiac hypertrophy.
小干扰 RNA（siRNA）治疗被认为是治疗心肌肥厚的一种强有力的治疗策略，心肌肥厚是随后发生心脏发病率和死亡率的重要危险因素。然而，siRNA 的安全有效的体内传递仍然是扩大其临床应用的主要挑战。小细胞外囊泡（sEVs）是 siRNA 的一种有前途的传递系统，但对细胞/组织的靶向能力有限。在这项研究中，通过使用基于生物正交无铜点击化学的简单、快速和可扩展的方法，将心脏靶向肽（CTP）缀合到人外周血衍生的 sEVs（PB-EVs）上，开发了新一代心脏靶向 sEVs（CEVs）。实验结果表明，CEVs 具有典型的 sEVs 特性和优异的心脏靶向能力。此外，为了治疗心肌肥厚，CEVs 负载 NADPH 氧化酶 4（NOX4）siRNA（siNOX4）。因此，CEVs@siNOX4 治疗通过 siRNA 保护和心脏靶向能力增强了 CEVs 的体外抗肥厚作用。此外，将 CEVs@siNOX4 静脉注射到血管紧张素 II（Ang II）处理的小鼠中，可显著改善心脏功能，减少纤维化和心肌细胞横截面积，且副作用有限。总之，CEVs 的利用代表了一种用于心脏靶向传递治疗性 siRNA 的有效策略，为心肌肥厚的治疗提供了很大的希望。
