Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents
Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents
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DOI：
10.1038/gt.2013.29
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发表时间：
2013-11-01
期刊：
影响因子：
5.1
通讯作者：
Jin, M. M.
中科院分区：
文献类型：
--
作者：
Kang, S.;Lu, K.;Jin, M. M.
很难实现大基因含量的系统性和靶向特异性递送。尽管病毒可以毫不费力地将长链DNA酶的基因组递送到细胞中，但其临床应用受到严重的安全性问题以及天然向性与所需靶点之间的不匹配的阻碍。相反，非病毒载体受到低基因转移效率和固有细胞毒性的限制。在这里，我们基于聚阴离子肽（PAP）、阳离子聚合物聚乙烯亚胺（PEI）和核酸之间的静电自组装设计了病毒模拟聚合物颗粒（VMP）。我们将PAP与整合素α（L）β（2）的工程配体结合域融合，以靶向细胞间粘附分子-1（ICAM-1），一种可诱导的炎症标志物。完全组装的VMPs包装大的遗传内容物，特异性地结合到靶分子，引起受体介导的内吞作用和逃逸的内体途径，类似于病毒的细胞内递送过程。与传统的PEI介导的转染不同，VMP的分子相互作用依赖性基因递送不受血清存在的影响，并且实现了更高的效率而没有毒性。通过靶向过表达的ICAM-1，VMP在体外和体内将基因特异性地递送到发炎的内皮细胞和巨噬细胞。该平台的简单性和多功能性以及炎症特异性递送可能为多方面的基因治疗开辟了机会，这些基因治疗可以转化为临床并治疗各种使人衰弱的免疫和炎症疾病。
Systemic and target-specific delivery of large genetic contents has been difficult to achieve. Although viruses effortlessly deliver kilobase-long genome into cells, its clinical use has been hindered by serious safety concerns and the mismatch between native tropisms and desired targets. Nonviral vectors, in contrast, are limited by low gene transfer efficiency and inherent cytotoxicity. Here we devised virus-mimetic polyplex particles (VMPs) based on electrostatic self-assembly among polyanionic peptide (PAP), cationic polymer polyethyleneimine (PEI) and nucleic acids. We fused PAP to the engineered ligand-binding domain of integrin alpha(L)beta(2) to target intercellular adhesion molecule-1 (ICAM-1), an inducible marker of inflammation. Fully assembled VMPs packaged large genetic contents, bound specifically to target molecules, elicited receptor-mediated endocytosis and escaped endosomal pathway, resembling intracellular delivery processes of viruses. Unlike conventional PEI-mediated transfection, molecular interaction-dependent gene delivery of VMPs was unaffected by the presence of serum and achieved higher efficiency without toxicity. By targeting overexpressed ICAM-1, VMPs delivered genes specifically to inflamed endothelial cells and macrophages both in vitro and in vivo. Simplicity and versatility of the platform and inflammation-specific delivery may open up opportunities for multifaceted gene therapy that can be translated into the clinic and treat a broad range of debilitating immune and inflammatory diseases.