Despite considerable efforts to develop efficient carriers, the major target organ of short-interfering RNAs (siRNAs) remains limited to the liver. Expanding the application outside the liver is required to increase the value of siRNAs. Here we report on a novel platform targeted to muscular organs by conjugation of siRNAs with anti-CD71 Fab′ fragment. This conjugate showed durable gene-silencing in the heart and skeletal muscle for one month after intravenous administration in normal mice. In particular, 1μg siRNA conjugate showed significant gene-silencing in the gastrocnemius when injected intramuscularly. In a mouse model of peripheral artery disease, the treatment with myostatin-targeting siRNA conjugate by intramuscular injection resulted in significant silencing of myostatin and hypertrophy of the gastrocnemius, which was translated into the recovery of running performance. These data demonstrate the utility of antibody conjugation for siRNA delivery and the therapeutic potential for muscular diseases.

中文翻译：

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针对心脏和骨骼肌的抗体-siRNA偶联物的开发

尽管为开发有效的载体付出了巨大的努力，但短干扰RNA（siRNA）的主要靶器官仍然局限于肝脏。需要扩大肝脏以外的应用以增加siRNA的价值。在这里，我们报告了一种新型平台，该平台针对具有抗CD71 Fab'片段的siRNA的缀合，针对肌肉器官。在正常小鼠中静脉内给药后，该缀合物在心脏和骨骼肌中显示出持久的基因沉默，持续了一个月。特别是，肌肉注射1μgsiRNA偶联物在腓肠肌中表现出显着的基因沉默。在周围动脉疾病的小鼠模型中，肌注肌肉注射靶向肌生长抑制素的siRNA偶联物可导致肌生长抑制素显着沉默和腓肠肌肥大，转化为运行性能的恢复。这些数据证明了抗体偶联对于siRNA传递的实用性和对肌肉疾病的治疗潜力。