Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China.
College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
Expert Opin Drug Deliv. 2022 Apr;19(4):435-450. doi: 10.1080/17425247.2022.2063835. Epub 2022 Apr 15.
miRNA-derivative clinical nucleotide drugs (mdCNDs) effectively treat several diseases, with numerous undergoing clinical trials. In early-stage trials in disease therapeutics, such as malignant pleural mesothelioma and hepatic virus C infection, mdCND's therapeutic potency is undeniably good for effectiveness and safety.
Fifteen mdCNDs undergoing clinical trials are introduced in this review. MiRNA modifications methods have been summarized, including phosphorothioate, cholesterol, locked nucleic acid, 2'-O-methyl, N,N-diethyl-4-(4-nitronaphthalen1-ylazo)-phenylamine modifications, and many more. Moreover, delivery systems, including self-assembled, inorganic ions nanoparticles, exosomes, and lipid-based nanosystems for mdCNDs targeted delivery, are presented. Among that, EnGeneIC, N-Acetylgalactosamine, liposomal nanoparticles, and cholesterol-conjugated for mdCNDs delivery are currently undergoing clinical trials. The pH, light, temperature, redox-responsive, enzyme, and specific-substance modes to trigger the release of miRNAs to target sites on-demand and the prospects of mdCNDs are discussed in this review.
mdNCDs are one type of promising clinical drugs, however, it is still in the infancy. During the development process, it is imperative to advance in modifying miRNAs, especially at the 5'-end, to enhance targetability and stability against nucleases, develop a stimuli-responsive mode to control the release of mdCNDs to tissue cell-type-specific sites.
miRNA 衍生的临床核苷酸药物（mdCND）有效地治疗了多种疾病，许多正在进行临床试验。在疾病治疗的早期临床试验中，如恶性胸膜间皮瘤和丙型肝炎病毒感染，mdCND 的治疗效果和安全性无疑很好。
本文综述了正在进行临床试验的 15 种 mdCND。总结了 miRNA 修饰方法，包括硫代磷酸酯、胆固醇、锁核酸、2'-O-甲基、N，N-二乙基-4-（4-硝基萘-1-基偶氮）-苯甲胺修饰等。此外，还介绍了用于 mdCND 靶向递送的自组装、无机离子纳米粒子、外泌体和基于脂质的纳米系统等递送系统。其中，EnGeneIC、N-乙酰半乳糖胺、脂质纳米粒和胆固醇缀合物目前正在进行临床试验。本文讨论了 pH 值、光、温度、氧化还原响应、酶和特异性物质等模式，以按需触发 miRNA 释放到靶位，并讨论了 mdCND 的前景。
mdNCD 是一种很有前途的临床药物，但仍处于起步阶段。在开发过程中，必须改进 miRNA 的修饰，特别是在 5'-端，以增强靶向性和对核酸酶的稳定性，开发一种对刺激有响应的模式来控制 mdCND 释放到组织细胞类型特异性部位。
