College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
Interdisciplinary Biophysics Graduate Program, College of Art and Science, The Ohio State University, Columbus, OH 43210, United States.
Adv Drug Deliv Rev. 2022 Jul;186:114316. doi: 10.1016/j.addr.2022.114316. Epub 2022 May 5.
Besides mRNA, rRNA, and tRNA, cells contain many other noncoding RNA that display critical roles in the regulation of cellular functions. Human genome sequencing revealed that the majority of non-protein-coding DNA actually codes for non-coding RNAs. The dynamic nature of RNA results in its motile and deformative behavior. These conformational transitions such as the change of base-pairing, breathing within complemented strands, and pseudoknot formation at the 2D level as well as the induced-fit and conformational capture at the 3D level are important for their biological functions including regulation, translation, and catalysis. The dynamic, motile and catalytic activity has led to a belief that RNA is the origin of life. We have recently reported that the deformative property of RNA nanoparticles enhances their penetration through the leaky blood vessel of cancers which leads to highly efficient tumor accumulation. This special deformative property also enables RNA nanoparticles to pass the glomerulus, overcoming the filtration size limit, resulting in fast renal excretion and rapid body clearance, thus low or no toxicity. The biodistribution of RNA nanoparticles can be further improved by the incorporation of ligands for cancer targeting. In addition to the favorable biodistribution profiles, RNA nanoparticles possess other properties including self-assembly, negative charge, programmability, and multivalency; making it a great material for pharmaceutical applications. The intrinsic negative charge of RNA nanoparticles decreases the toxicity of drugs by preventing nonspecific binding to the negative charged cell membrane and enhancing the solubility of hydrophobic drugs. The polyvalent property of RNA nanoparticles allows the multi-functionalization which can apply to overcome drug resistance. This review focuses on the summary of these unique properties of RNA nanoparticles, which describes the mechanism of RNA dynamic, motile and deformative properties, and elucidates and prepares to welcome the RNA therapeutics as the third milestone in pharmaceutical drug development.
除了 mRNA、rRNA 和 tRNA 之外，细胞还含有许多其他非编码 RNA，它们在调节细胞功能方面发挥着关键作用。人类基因组测序表明，大多数非蛋白编码 DNA实际上编码非编码 RNA。RNA 的动态性质导致其具有运动和变形的行为。这些构象转换，如碱基对的改变、互补链内的呼吸以及二维水平上的假结形成，以及三维水平上的诱导契合和构象捕获，对于它们的生物学功能（包括调节、翻译和催化）非常重要。动态、运动和催化活性使得人们相信 RNA 是生命的起源。我们最近报告称，RNA 纳米颗粒的变形特性增强了它们穿透癌症渗漏血管的能力，从而导致高效的肿瘤积累。这种特殊的变形特性还使 RNA 纳米颗粒能够通过肾小球，克服过滤尺寸限制，导致快速的肾脏排泄和快速的全身清除，从而导致低或无毒性。通过掺入用于癌症靶向的配体，可以进一步改善 RNA 纳米颗粒的生物分布。除了有利的生物分布特征外，RNA 纳米颗粒还具有其他特性，包括自组装、负电荷、可编程性和多价性；使其成为药物应用的理想材料。RNA 纳米颗粒的固有负电荷通过防止与带负电荷的细胞膜非特异性结合并提高疏水性药物的溶解度来降低药物的毒性。RNA 纳米颗粒的多价性允许多功能化，可应用于克服药物耐药性。这篇综述重点介绍了 RNA 纳米颗粒的这些独特特性，描述了 RNA 动态、运动和变形特性的机制，并阐明和准备迎接 RNA 治疗作为药物开发的第三个里程碑。
