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首页> 外文期刊>ACS applied materials & interfaces >Efficient and Robust Highly Branched Poly(beta-amino ester)/Minicircle COL7A1 Polymeric Nanoparticles for Gene Delivery to Recessive Dystrophic Epidermolysis Bullosa Keratinocytes
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Efficient and Robust Highly Branched Poly(beta-amino ester)/Minicircle COL7A1 Polymeric Nanoparticles for Gene Delivery to Recessive Dystrophic Epidermolysis Bullosa Keratinocytes

机译：高效且坚固的高度分支聚（β-氨基酯）/迷你岩COL7A1聚合物纳米颗粒用于基因递送至隐性营养不良表皮细胞Bullosa角蛋白细胞

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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe congenital skin fragility disease caused by COL7A1 mutations that result in type VII collagen (C7) deficiency. Herein, we report a synergistic polyplex system that can efficiently restore C7 expression in RDEB keratinocytes. A highly branched multifunctional poly(beta-amino ester) (HPAE), termed as HC32-122, was optimized systematically as the high-performance gene delivery vector for keratinocytes, achieving much higher transfection capability than polyethylenimine, SuperFect, and Lipofectamine 2000 without inducing obvious cytotoxicity. Concurrently, a 12 kb length minicircle DNA encoding similar to 9 kb full-length COL7A1 (MCC7) devoid of bacterial sequence was biosynthesized as the therapeutic gene. Combining the highly potent polymer and the miniaturized gene structure, HC32-122/MCC7 polyplexes achieve 96.4% cellular uptake efficiency, 4019-fold COL7A1 mRNA enhancement, and robust recombinant C7 expression. Structure-property investigations reveal that HC32-122 can effectively condense MCC7 to form small, uniform, compact, and positively charged spherical nanoparticles with high DNA release flexibility. Moreover, formulation study shows that sucrose is conductive to lyophilized HC32-122/DNA polyplexes for maintaining the transfection capability. Direct frozen polyplexes can maintain full gene transfection capability after one-year storage. High efficiency, biocompatibility, facile manipulation, and long-term stability make the HC32-122/MCC7 system a promising bench-to-bed candidate for treating the debilitating RDEB.
机译：隐性营养不良表皮分解Bullosa（RDeb）是由Col7A1突变引起的严重先天性皮肤脆性，导致VII型胶原蛋白（C7）缺乏。在此，我们报告了一种协同性多移系统，可以有效地恢复RDEB角质形成细胞中的C7表达。作为HC32-122称为HC32-122的高度分枝多官能聚（β-氨基酯）（HPAE）被系统地作为角质形成细胞的高性能基因递送载体进行优化，比聚乙胺，超细和Lipofectamine 2000的转染能力更高，而不会诱导明显的细胞毒性。同时，一种类似于9 kB全长COL7A1（MCC7）的12kB长度小循环DNA，其具有细菌序列的细菌序列是生物合成的，作为治疗基因。结合高效的聚合物和小型化基因结构，HC32-122 / MCC7多方达到96.4％的细胞吸收效率，4019倍的COL7A1 mRNA增强和鲁棒重组C7表达。结构性研究表明，HC32-122可以有效地凝结MCC7，形成具有高DNA释放柔韧性的小，均匀，紧凑，带正电的球形纳米颗粒。此外，制剂研究表明，蔗糖导致冻干的HC 3 2 -122 / DNA多种，用于保持转染能力。直接冷冻的多重可以在一年储存后保持全基因转染能力。高效率，生物相容性，容易操纵和长期稳定性使HC32-122 / MCC7系统成为治疗衰弱的RDEB的有前途的台面候选者。

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