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.

中文翻译：

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工程化小细胞外囊泡介导的 NOX4 siRNA 递送用于心脏肥大的靶向治疗

小干扰RNA (siRNA) 疗法被认为是治疗心脏肥大的有效治疗策略，心脏肥大是随后心脏发病和死亡的重要危险因素。然而，缺乏安全有效的体内递送siRNA是扩大其临床应用的主要挑战。小细胞外囊泡 (sEV) 是一种很有前途的 siRNA 递送系统，但其细胞/组织特异性靶向能力有限。在这项研究中，通过将心脏靶向肽（CTP）与人外周血来源的 sEV（PB-EV）结合，使用基于生物正交无铜点击化学。实验结果表明，CEV具有典型的sEV特性和优异的心脏靶向能力。此外，为了治疗心脏肥大，CEV 负载有 NADPH 氧化酶 4 (NOX4) siRNA (siNOX4)。因此，CEVs@siNOX4 治疗增强了具有 siRNA 保护和心脏靶向能力的 CEVs 的体外抗肥厚作用。此外，向血管紧张素II（Ang II）治疗的小鼠静脉注射CEVs@siNOX4可显着改善心脏功能，减少纤维化和心肌细胞横截面积，且副作用有限。总之，CEV 的利用代表了治疗性 siRNA 的心脏靶向递送的有效策略，并为心脏肥大的治疗带来了巨大的希望。