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Macrophage-targeting and reactive oxygen species (ROS)-responsive nanopolyplexes mediate anti-inflammatory siRNA delivery against acute liver failure (ALF)†
Biomaterials Science ( IF 6.6 ) Pub Date : 2018-05-10 00:00:00 , DOI: 10.1039/c8bm00389k
Wenxin Zhang 1, 2, 3, 4, 5 , Yang Zhou 1, 2, 3, 4, 5 , Xudong Li 1, 2, 3, 4, 5 , Xin Xu 1, 2, 3, 4, 5 , Yongbing Chen 6, 7, 8, 9 , Rongying Zhu 6, 7, 8, 9 , Lichen Yin 1, 2, 3, 4, 5
Affiliation  

As one of the intractable challenges in the clinic, the treatment of acute liver failure (ALF) is limited due to high mortality and resource cost. RNA interference (RNAi) provides a new modality for the anti-inflammatory therapy of ALF, while its therapeutic efficacy is greatly hampered by the lack of effective carriers to cooperatively overcome the various systemic barriers. Herein, we developed macrophage-targeting and reactive oxygen species (ROS)-responsive polyplexes to enable efficient systemic delivery of TNF-α siRNA (siTNF-α) to attenuate hepatic inflammation in mice bearing ALF. Se-PEI, obtained from the cross-linking of 600 Da polyethylenimine (PEI) via the ROS-responsive diselenide bond, was developed to condense siTNF-α, and the obtained polyplexes were further coated with carboxylated mannan (Man-COOH). Man-COOH coating allowed active targeting of polyplexes to macrophages with over-expressed mannose receptors (MRs), and it shielded the surface positive charges to enhance the serum stability of polyplexes. Se-PEI could be degraded by ROS in inflammatory macrophages to promote intracellular siRNA release to potentiate the gene knockdown efficiency, and in the meantime reduce the material cytotoxicity associated with high molecular weight. As such, i.v. injected Man-COOH/Se-PEI/siTNF-α polyplexes afforded notable TNF-α silencing by ∼80% in inflamed liver tissues at 500 μg siRNA per kg, and notably reduced serum TNF-α levels to achieve potent anti-inflammatory performance against ALF.

中文翻译:

靶向巨噬细胞和活性氧(ROS)的纳米复合物介导针对急性肝衰竭(ALF)的抗炎siRNA传递

作为临床上棘手的挑战之一,由于高死亡率和资源成本,治疗急性肝衰竭(ALF)受到了限制。RNA干扰(RNAi)为ALF的抗炎治疗提供了一种新的方式,同时由于缺乏有效克服各种系统性障碍的有效载体,极大地阻碍了其治疗效果。在这里,我们开发了针对巨噬细胞和活性氧(ROS)响应的复合体,以使TNF-αsiRNA(siTNF-α)的有效全身传递,以减轻荷ALF小鼠的肝炎。Se-PEI,是通过600 Da聚乙烯亚胺(PEI)通过研发出ROS反应性二硒键以凝聚siTNF-α,然后将所得的复合物进一步用羧化甘露聚糖(Man-COOH)包被。Man-COOH涂层可将多聚体主动靶向至过表达甘露糖受体(MRs)的巨噬细胞,并且它屏蔽了表面的正电荷,从而增强了多聚体的血清稳定性。ROS在炎性巨噬细胞中可以降解Se-PEI,从而促进细胞内siRNA的释放,从而增强基因的敲除效率,同时降低与高分子量有关的物质细胞毒性。因此,静脉注射Man-COOH / Se-PEI /siTNF-α复合物在发炎的肝组织中以每公斤500μgsiRNA的浓度提供了约80%的显着TNF-α沉默,并显着降低了血清TNF-α的水平以实现有效的抗-针对ALF的炎症表现。
更新日期:2018-05-10
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