Advances in modification and delivery of nucleic acid drugs

Nucleic acid drugs are oligo RNA or oligo DNA in molecular structure that function at the genetic level. There are many types of nucleic acid drugs are available at present like aptamer, antisense oligonucleotide, mRNA, miRNA, siRNA, saRNA and so on. The nucleic acid drugs have high specificity, however, they face challenges in clinical applications, such as short half-life, poor stability, and susceptibility to endogenous nucleases. Their stability, physicochemical properties, affinity, and targeting can be improved through nucleic acid structure modification. Meanwhile, the nucleic acid carriers are conducive to drugs penetrating cell membrane to further enhance their stability and targeting properties, and facilitating their efficient intracellular escape to exert therapeutic effects. The delivery carriers including virus vectors, lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, protein carriers, and extracellular vesicles are commonly used currently. A combination of various modification method and drug delivery system is necessary to achieve better clinical therapeutic outcomes. This article reviews the research progress in characteristics, the structure modification methods, delivery systems and the further development of nucleic acid drugs, to provide a reference for the future clinical translational application of nucleic acid drugs.核酸类药物是在基因水平上发挥作用的寡聚RNA或寡聚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。尽管核酸类药物具有高度特异性，但在临床应用过程中，却面临半衰期短、稳定性差、易被内源性核酸酶水解等难题。通过核酸结构修饰可以提高其在体内的稳定性，改善理化性质，提高亲和性和靶向性；应用核酸类药物载体可以帮助药物跨膜到达特定的组织和细胞，进一步增强核酸类药物的稳定性和靶向性，帮助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。将多种修饰和药物递送方法组合起来，共同发挥作用，才能较好满足临床治疗要求。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。.