Suppression of Hepatic Inflammation via Systemic siRNA Delivery by Membrane-Disruptive and Endosomolytic Helical Polypeptide Hybrid Nanoparticles

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• 作者：Hua He ; Nan Zheng ; Ziyuan Song ; Kyung Hoon Kim ; Catherine Yao ; Rujing Zhang ; Chenglin Zhang ; Yuhui Huang ; Fatih M. Uckun ; Jianjun Cheng ; Yanfeng Zhang ; Lichen Yin
• 刊名：ACS Nano
• 出版年：2016
• 出版时间：February 23, 2016
• 年：2016
• 卷：10
• 期：2
• 页码：1859-1870
• 全文大小：599K
• ISSN：1936-086X

文摘

Treatment of inflammatory diseases represents one of the biggest clinical challenges. RNA interference (RNAi) against TNF-α provides a promising modality toward anti-inflammation therapy, but its therapeutic potential is greatly hampered by the by the lack of efficient siRNA delivery vehicles in vivo. Herein, we report a hybrid nanoparticulate (HNP) system based on a cationic helical polypeptide PPABLG for the efficient delivery of TNF-α siRNA. The helical structure of PPABLG features pore formation on cellular and endosomal membranes to facilitate the direct translocation as well as endosomal escape of TNF-α siRNA in macrophages, representing a unique superiority to a majority of the existing polycation-based gene vectors that experience severe endosomal entrapment and lysosomal degradation. As such, HNPs containing TNF-α siRNA afforded effective systemic TNF-α knockdown following systemic administration at a low dose of 50 μg of siRNA/kg and thus demonstrated a potent anti-inflammatory effect to rescue animals from LPS/d-GalN-induced hepatic sepsis. This study therefore verifies that the bioactive secondary structure of polypeptides significantly dominates the in vivo siRNA delivery efficiency, and the unique properties of PPABLG HNPs render remarkable potentials for anti-inflammation therapies.