Anand Puneet, Zhang Yu, Patil Spoorthi, Kaur Keerat
Regeneron Genetic Medicines, Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, United States.
J Med Chem. 2025 Apr 10;68(7):6870-6896. doi: 10.1021/acs.jmedchem.4c02528. Epub 2025 Jan 8.
Oligonucleotides have emerged as a formidable new class of nucleic acid therapeutics. Fully modified oligonucleotides exhibit enhanced metabolic stability and display successful clinical applicability for targets formerly considered "undruggable". Accumulating studies show that conjugation to targeting modalities of stabilized oligonucleotides, especially small interfering RNAs (siRNAs), has enabled robust delivery to intended cells/tissues. However, the major challenge in the field has been the stability and targeted delivery of oligonucleotides (siRNAs and antisense oligonucleotides (ASOs)) to extrahepatic tissues. In this Perspective, we review chemistry innovations and emerging delivery approaches that have revolutionized oligonucleotide drug discovery and development. We explore findings from both academia and industry that highlight the potential of oligonucleotides for indications involving different extrahepatic organs─including skeletal muscles, brain, lungs, skin, heart, adipose tissue, and eyes. In all, continued advances in chemistry coupled with conjugation-based approaches or novel administration routes will further advance the delivery of oligonucleotides to extrahepatic tissues.
寡核苷酸已成为一类强大的新型核酸疗法。完全修饰的寡核苷酸具有更高的代谢稳定性，并在针对以前被认为“不可成药”的靶点方面展现出成功的临床适用性。越来越多的研究表明，将稳定化寡核苷酸，尤其是小干扰RNA（siRNA）与靶向方式偶联，能够实现向目标细胞/组织的有效递送。然而，该领域的主要挑战一直是寡核苷酸（siRNA和反义寡核苷酸（ASO））向肝外组织的稳定性和靶向递送。在这篇观点文章中，我们回顾了化学创新以及新兴的递送方法，这些创新和方法彻底改变了寡核苷酸药物的发现和开发。我们探讨了来自学术界和工业界的研究结果，这些结果突出了寡核苷酸在涉及不同肝外器官（包括骨骼肌、脑、肺、皮肤、心脏、脂肪组织和眼睛）的适应症中的潜力。总之，化学方面的持续进步以及基于偶联的方法或新型给药途径将进一步推动寡核苷酸向肝外组织的递送。
