Lam Yuen Ting, Lee Bob S L, Hung Juichien, Michael Praveesuda, Santos Miguel, Tan Richard P, Liu Renjing, Wise Steven G
Chronic Diseases Theme, School of Medical Science, University of Sydney, Sydney 2006, Australia.
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia.
Nanomaterials (Basel). 2023 Aug 18;13(16):2360. doi: 10.3390/nano13162360.
MicroRNAs (miRNAs) are increasingly recognised as key regulators of the development and progression of many diseases due to their ability to modulate gene expression post-translationally. While this makes them an attractive therapeutic target, clinical application of miRNA therapy remains at an early stage and in part is limited by the lack of effective delivery modalities. Here, we determined the feasibility of delivering miRNA using a new class of plasma-polymerised nanoparticles (PPNs), which we have recently isolated and characterised. We showed that PPN-miRNAs have no significant effect on endothelial cell viability in vitro in either normal media or in the presence of high-glucose conditions. Delivery of a miRNA inhibitor targeting miR-503 suppressed glucose-induced miR-503 upregulation and restored the downstream mRNA expression of and in endothelial cells. Subsequently, PPN delivery of miR-503 inhibitors enhanced endothelial angiogenesis, including tubulogenesis and migration, in culture conditions that mimic diabetic ischemia. An intramuscular injection of a PPN-miR-503 inhibitor promoted blood-perfusion recovery in the hindlimb of diabetic mice following surgically induced ischemia, linked with an increase in new blood vessel formation. Together, this study demonstrates the effective use of PPN to deliver therapeutic miRNAs in the context of diabetes.
微小RNA（miRNA）越来越被认为是许多疾病发生发展的关键调节因子，因为它们能够在翻译后水平调节基因表达。尽管这使得它们成为有吸引力的治疗靶点，但miRNA疗法的临床应用仍处于早期阶段，部分原因是缺乏有效的递送方式。在此，我们确定了使用一类新型的等离子体聚合纳米颗粒（PPN）递送miRNA的可行性，我们最近已对其进行了分离和表征。我们发现，在正常培养基或高糖条件下，PPN-miRNA对体外内皮细胞活力均无显著影响。递送靶向miR-503的miRNA抑制剂可抑制葡萄糖诱导的miR-503上调，并恢复内皮细胞中相关基因的下游mRNA表达。随后，在模拟糖尿病缺血的培养条件下，PPN递送miR-503抑制剂可增强内皮细胞血管生成，包括管腔形成和迁移。肌肉注射PPN-miR-503抑制剂可促进手术诱导缺血后糖尿病小鼠后肢的血液灌注恢复，这与新血管形成增加有关。总之，本研究证明了PPN在糖尿病背景下有效递送治疗性miRNA的作用。
