Advances in modification and delivery of nucleic acid drugs

Nucleic acid-based drugs, such as RNA and DNA drugs, exert their effects at the genetic level. Currently, widely utilized nucleic acid-based drugs include nucleic acid aptamers, antisense oligonucleotides, mRNA, miRNA, siRNA and saRNA. However, these drugs frequently encounter challenges during clinical application, such as poor stability, weak targeting specificity, and difficulties in traversing physiological barriers. By employing chemical modifications of nucleic acid structures, it is possible to enhance the stability and targeting specificity of certain nucleic acid drugs within the body, thereby improving delivery efficiency and reducing immunogenicity. Moreover, utilizing nucleic acid drug carriers can facilitate the transportation of drugs to lesion sites, thereby aiding efficient intracellular escape and promoting drug efficacy within the body. Currently, commonly employed delivery carriers include virus vectors, lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, protein carriers and extracellular vesicles. Nevertheless, individual modifications or delivery carriers alone are insufficient to overcome numerous obstacles. The integration of nucleic acid chemical modifications with drug delivery systems holds promise for achieving enhanced therapeutic effects. However, this approach also presents increased technical complexity and clinical translation costs. Therefore, the development of nucleic acid drug carriers and nucleic acid chemical modifications that are both practical and simple, while maintaining high efficacy, low toxicity, and precise nucleic acid delivery, has become a prominent research focus in the field of nucleic acid drug development. This review comprehensively summarizes the advancements in nucleic acid-based drug modifica-tions and delivery systems. Additionally, strategies to enhance nucleic acid drug delivery efficiency are discussed, with the aim of providing valuable insights for the translational application of nucleic acid drugs.核酸类药物是在基因水平上发挥作用的RNA或DNA。目前应用较多的有核酸适配体、反义寡核苷酸、信使RNA、微RNA、小干扰RNA、小激活RNA等。核酸类药物临床应用面临稳定性差、靶向性弱、难以跨越体内屏障等难题。通过核酸化学结构修饰可以提高部分核酸药物在体内的稳定性、靶向性，提高递送效率，同时降低药物的免疫原性；应用核酸类药物载体可以帮助药物到达病灶，有助于核酸类药物实现更高效的内体逃逸，促进药物在体内发挥作用。目前应用较多的递送载体有病毒载体、脂质纳米粒、聚合物纳米载体、无机纳米载体、蛋白载体、外泌体等。目前，单独的修饰或递送载体尚不足以克服众多障碍，将核酸化学结构修饰与药物递送系统相结合有望实现更好的治疗效果，但后者技术难度和临床转化成本也随之增加。针对更加简单实用、低毒高效、精准递送核酸药物载体和核酸化学结构修饰的研发将成为核酸药物研发的热点方向。本文综述了核酸类药物的修饰和递送研究进展，讨论了提高核酸类药物递送效率的对策，以期为核酸类药物的转化应用提供参考。.