Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, 100871, China.
Nanoscale. 2019 Oct 10;11(39):18052-18064. doi: 10.1039/c9nr05758g.
Nanomaterials hold promise for the delivery of nucleic acids to facilitate gene therapy in cardiac diseases. However, as much of the in vivo study of nanomaterials was conducted via the "trial and error" method, the understanding of the nanomaterial-mediated delivery in cardiac tissue was limited to the gross efficiency in manipulating the gene expression while little was known about the delivery process and mechanism in particular at the cell level. In this study, small interfering RNA (siRNA) nanoparticles formulated with a polyamidoamine (PAMAM) nanomaterial were applied to the injured heart of zebrafish. The distribution of nanoparticles in cardiomyocytes, endothelial cells, macrophages and leukocytes was quantitatively analyzed with precision at the cell level by using transgenic models. Based on the distribution characteristics, gene silencing effects in a specific group of cells were analyzed to illustrate how siRNA nanoparticles could get potent gene silencing in different cells in vivo. The results elucidated the heterogeneous distribution of siRNA nanoparticles and how nanoparticles could be efficient despite the significant difference in cellular uptake efficiency in different cells. It demonstrated a paradigm and the need to decouple cellular processes to understand nanoparticle-mediated delivery in complex tissue and the investigation/methodology may lead to important information to guide the design of advanced targeted drug-delivery systems in heart.
纳米材料有望用于递送核酸，以促进心脏疾病的基因治疗。然而，由于大多数纳米材料的体内研究都是通过“反复试验”的方法进行的，因此对纳米材料介导的心脏组织内递送的理解仅限于操纵基因表达的总体效率，而对于递送过程和机制，特别是在细胞水平上，了解甚少。在这项研究中，用一种聚酰胺胺（PAMAM）纳米材料制备的小干扰 RNA（siRNA）纳米颗粒被应用于斑马鱼的受损心脏。利用转基因模型，在细胞水平上对纳米颗粒在心肌细胞、内皮细胞、巨噬细胞和白细胞中的分布进行了精确的定量分析。基于分布特征，分析了特定细胞群中的基因沉默效果，以说明 siRNA 纳米颗粒如何在体内对不同细胞产生有效的基因沉默。结果阐明了 siRNA 纳米颗粒的异质性分布，以及尽管不同细胞的细胞摄取效率存在显著差异，但纳米颗粒如何能够高效传递。这证明了一种范例和需要分离细胞过程，以理解复杂组织中纳米颗粒介导的递送，并且该研究/方法可能会提供重要信息，以指导心脏中先进靶向药物递送系统的设计。
