Oligonucleotide gene therapy has shown great promise for the treatment of muscular dystrophies. Nevertheless, the selective delivery to affected muscles has shown to be challenging because of their high representation in the body and the high complexity of their cell membranes. Current trials show loss of therapeutic molecules to non-target tissues leading to lower target efficacy. Therefore, strategies that increase uptake efficiency would be particularly compelling. To address this need, we applied a cell-internalization SELEX (Systematic Evolution of Ligands by Exponential Enrichment) approach and identified a skeletal muscle-specific RNA aptamer. A01B RNA aptamer preferentially internalizes in skeletal muscle cells and exhibits decreased affinity for off-target cells. Moreover, this in vitro selected aptamer retained its functionality in vivo, suggesting a potential new approach for targeting skeletal muscles. Ultimately, this will aid in the development of targeted oligonucleotide therapies against muscular dystrophies.

寡核苷酸基因疗法已显示出治疗肌营养不良症的巨大希望。然而，由于其在体内的高表达和其细胞膜的高度复杂性，向受累肌肉的选择性递送已显示出挑战性。当前的试验表明治疗分子向非靶标组织的损失导致较低的靶标功效。因此，提高吸收效率的策略将特别引人注目。为了满足这一需求，我们应用了细胞内在化SELEX（通过指数富集进行配体的系统进化）方法，并确定了骨骼肌特异性RNA适体。A01B RNA适体优先在骨骼肌细胞中内在化，并且对脱靶细胞的亲和力降低。而且，这种体外选定的适体在体内保留了其功能，这表明了一种潜在的靶向骨骼肌的新方法。最终，这将有助于开发针对肌肉营养不良的靶向寡核苷酸疗法。