Oligonucleotide therapeutics hold promise for the treatment of muscle- and heart-related diseases. However, oligonucleotide delivery across the continuous endothelium of muscle tissue is challenging. Here, we demonstrate that docosanoic acid (DCA) conjugation of small interfering RNAs (siRNAs) enables efficient (~5% of injected dose), sustainable (>1 month), and non-toxic (no cytokine induction at 100 mg/kg) gene silencing in both skeletal and cardiac muscles after systemic injection. When designed to target myostatin (muscle growth regulation gene), siRNAs induced ~55% silencing in various muscle tissues and 80% silencing in heart, translating into a ~50% increase in muscle volume within 1 week. Our study identifies compounds for RNAi-based modulation of gene expression in skeletal and cardiac muscles, paving the way for both functional genomics studies and therapeutic gene modulation in muscle and heart.

寡核苷酸疗法有望治疗肌肉和心脏相关疾病。然而，跨肌肉组织连续内皮的寡核苷酸递送具有挑战性。在这里，我们证明，二十二烷酸 (DCA) 与小干扰 RNA (siRNA) 的结合可实现高效（约注射剂量的 5%）、可持续（> 1 个月）和无毒（100 mg/kg 时无细胞因子诱导）全身注射后骨骼肌和心肌中的基因沉默。当设计以肌肉生长抑制素（肌肉生长调节基因）为目标时，siRNA 在各种肌肉组织中诱导约 55% 的沉默，在心脏中诱导 80% 的沉默，转化为 1 周内肌肉体积增加约 50%。我们的研究确定了基于 RNAi 的骨骼肌和心肌基因表达调节化合物，为功能基因组学研究和肌肉和心脏的治疗性基因调节铺平了道路。