ARC Centre of Excellence for Functional Nanomaterials, The University of Queensland, Queensland 4072, Australia.
Biomaterials. 2010 Nov;31(33):8770-9. doi: 10.1016/j.biomaterials.2010.07.077. Epub 2010 Aug 14.
Small interfering RNAs (siRNAs) are capable of targeting and destroying specific mRNAs, making them particularly suited to the treatment of neurodegenerative conditions such as Huntington's Disease where the production of abnormal proteins results in a gain-of-function phenotype. Although a variety of nanoparticle formulations are currently under development as siRNA delivery systems, application of these technologies has been limited by their high cytotoxicity, low drug loading capacity and release, and inability to penetrate cell membranes. Layered double hydroxide (LDH) nanoparticles are now emerging as a potential new drug delivery system as they exhibit low cytotoxicity and are highly biocompatible. Here we present the first study investigating LDH delivery of siRNAs to primary cultured neurons. We show that internalization by neurons is rapid, dose-dependent and saturable, and markedly more efficient than in other cell types. We demonstrate that siRNA-LDH complexes are internalized by clathrin-dependent endocytosis at the cell body and in neurites, with subsequent retrograde transport to the cell body followed by efficient release into the cytoplasm. Finally we show that LDH mediated siRNA delivery effectively silences neuronal gene expression. This study therefore confirms the potential of LDH nanoparticles as a drug delivery system for patients suffering from neurodegenerative disease.
小干扰 RNA（siRNAs）能够靶向并破坏特定的 mRNA，使其特别适合于治疗神经退行性疾病，如亨廷顿病，其中异常蛋白质的产生导致功能获得表型。尽管目前正在开发各种纳米颗粒制剂作为 siRNA 递送系统，但这些技术的应用受到其高细胞毒性、低药物载量和释放以及无法穿透细胞膜的限制。层状双氢氧化物（LDH）纳米颗粒现在作为一种潜在的新型药物递送系统出现，因为它们表现出低细胞毒性和高度生物相容性。在这里，我们首次研究了 LDH 向原代培养神经元递送 siRNA。我们表明，神经元的内化是快速的、剂量依赖性的和饱和的，并且明显比其他细胞类型更有效。我们证明 siRNA-LDH 复合物通过网格蛋白依赖性内吞作用在细胞体和神经突中内化，随后逆行运输到细胞体，随后有效释放到细胞质中。最后，我们表明 LDH 介导的 siRNA 递送可有效沉默神经元基因表达。因此，这项研究证实了 LDH 纳米颗粒作为治疗神经退行性疾病患者的药物递送系统的潜力。
