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首页> 外文期刊>Biomaterials >Injectable nanofibrous spongy microspheres for NR4A1 plasmid DNA transfection to reverse fibrotic degeneration and support disc regeneration
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Injectable nanofibrous spongy microspheres for NR4A1 plasmid DNA transfection to reverse fibrotic degeneration and support disc regeneration

机译：用于NR4A1质粒DNA转染的可注射纳米纤维海绵微球，反向纤维化变性和支撑盘再生

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Safe and efficient gene therapy is highly desired for controlling pathogenic fibrosis of nucleus pulposus (NP) tissue, which would result in intervertebral disc (IVD) degeneration and disability if left untreated. In this work, a hyperbranched polymer (HP) with high plasmid DNA (pDNA) binding affinity and negligible cytotoxicity is synthesized, which can self-assemble into nano-sized polyplexes with a "double shell" structure that can transfect pDNA into NP cells with very high efficiency. These polyplexes are then encapsulated in biodegradable nanospheres (NS) to enable two-stage delivery: 1) temporally-controlled release of pDNA-carrying polyplexes and 2) highly efficient delivery of pDNA into cells by the released polyplexes. These biodegradable NS are co-injected with nanofibrous spongy microspheres (NF-SMS) to localize the cellular transfection of the pDNA encoding orphan nuclear receptor 4A1 (NR4A1), which was recently reported as a therapeutic agent to delay pathogenic fibrosis. It is shown that HP can transfect human NP cells efficiently in vitro with low cytotoxicity. The two-stage delivery system is able to present the polyplexes over a sustained time period (more than 30 days) in the tail of a rat. The NR4A1 pDNA carried by the HP polyplexes is found to therapeutically reduce the pathogenic fibrosis of NP tissue in a rat-tail degeneration model. In conclusion, the combination of the two-stage NR4A1 pDNA delivery NS and NF-SMS is able to repress fibrosis and to support IVD regeneration. (C) 2017 Elsevier Ltd. All rights reserved.
机译：对于控制核瓜素（NP）组织的致病性纤维化，非常需要安全和有效的基因治疗，这将导致椎间盘（IVD）变性和残疾如果留下未处理。在这项工作中，合成了具有高质粒DNA（PDNA）结合亲和力和可忽略的细胞毒性的超支化聚合物（HP），其可以自组装成具有“双壳”结构的纳米尺寸的聚包，其可以将PDNA转染到NP细胞中效率很高。然后将这些多重包封在可生物降解的纳米球（NS）中，以使两级递送：1）通过释放的多重高效地将PDNA递送到细胞中。这些可生物降解的NS用纳米纤维海绵状微球（NF-SMS）共注出，以定位编码孤儿核受体4A1（NR4A1）的PDNA的细胞转染，其最近将作为治疗剂延迟致病性纤维化的治疗剂。结果表明，HP可以用低细胞毒性有效地转发人NP细胞。两级输送系统能够在大鼠尾部在持续的时间段（超过30天）上呈现多方。通过HP多用途携带的NR4A1 PDNA在大鼠尾变性模型中治疗降低NP组织的致病性纤维化。总之，两阶段NR4A1 PDNA递送NS和NF-SM的组合能够压制纤维化并支持IVD再生。 （c）2017 Elsevier Ltd.保留所有权利。

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