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西安交大雷波教授最新文章 将miRNA送过去调控干细胞分化

2017.1.21
西安交大科研人员采用层层组装技术在超小金纳米颗粒表面构建脂质体和聚乙烯亚胺膜层,研发出新型非病毒基因载体系统,该系统细胞毒性小,能够高效负载miRNA,防止miRNA酶降解,准确输送miRNA进入骨髓间充质干细胞,显著促进干细胞成骨分化,在基因输送领域显示出较好的应用前景。

这一研究成果公布在Nano Research杂志上。

干细胞的分化调控是近年来组织再生和组织工程领域的研究重点和研究热点,如何实现干细胞高效定向分化为特定类型组织的细胞已经成为再生医学领域的关键课题之一。

MiRNA 是一类新型的非编码小分子RNA(19~25t), 具有显著的基因转录后水平的调控功能,因此在细胞分化进程中起着重要的作用。然而miRNA在应用过程当中容易被酶降解而难以进入细胞发挥其调控作用,因如何高效地将miRNA递送进细胞并实现释放与靶基因结合是目前miRNA应用当中面临的主要挑战之一。

在一项新的研究当中,西安交通大学雷波教授课题组研发出了一种新型非病毒基因载体成功实现低毒高效的将miRNA输送到骨髓基质干细胞中,通过上调成骨基因的表达高效实现干细胞向成骨细胞分化和矿化。

金纳米颗粒因为其较好的生物相容性和稳定性,已经成为一种重要的基因递送载体材料,然而传统的金纳米基因载体尺寸大部分超过10nm,这类材料在体内难以降解或清除,因而存在潜在的长期毒性隐患,超小纳米材料(小于10nm)具有较好的肾清除能力,在药物递送领域具有重要的应用前景。课题组采用层层自组装技术制备了聚乙烯亚胺(PEI)和脂质体(Lipo)功能化的超小金纳米颗粒(Au@PEI@Lipo), 在体外成功把miRNA递送进骨髓基质干细胞(BMSCs),实现了高效的调控BMSCs的成骨分化和矿化。该载体系统在体外的miRNA细胞转染效率显著高于商用的基因转染试剂PEI 25KD和Lipofectamine 2000,并表现出超低的细胞毒性,在基因递送、疾病治疗和组织再生领域具有重要的应用潜力。

原文摘要:

Optimizing surface-engineered ultra-small gold nanoparticles for highly efficient miRNA delivery to enhance osteogenic differentiation of bone mesenchymal stromal cells

Regulation of osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) plays a critical role in bone regeneration. As small non-coding RNAs, microRNAs (miRNAs) play an important role in stem cell differentiation through regulating target-mRNA expression. Unfortunately, highly efficient and safe delivery of miRNAs to BMSCs to regulate their osteogenic differentiation remains challenging. Conventional inorganic nanocrystals have shown increased toxicity owing to their larger size precluding renal clearance. Here, we developed novel, surface-engineered, ultra-small gold nanoparticles (USAuNPs, <10 nm) for use as highly efficient miR-5106-delivery systems to enable regulation of BMSC differentiation. We exploited the effects of AuNPs coated layer-by-layer with polyethylenimine (PEI) and liposomes (Lipo) to enhance miR-5106-delivery activity and subsequent BMSC differentiation capacity. The PEI- and Lipo-coated AuNPs (Au@PEI@Lipo) showed negligible cytotoxicity, good miRNA-5106-binding affinity, highly efficient delivery of miRNAs to BMSCs, and long-term miRNA expression (21 days). Additionally, compared with commercial Lipofectamine 3000 and 25 kD PEI, the optimized Au@PEI@Lipo-miR-5106 nanocomplexes significantly enhanced BMSC differentiation into osteoblast-like cells through activation of the Sox9 transcription factor. Our findings reveal a promising strategy for the rational design of ultra-small inorganic nanoparticles as highly efficient miRNA-delivery platforms for tissue regeneration and disease therapy.


 

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