title: Suppression of Hepatic Inflammation via Systemic siRNA Delivery by Membrane-Disruptive and Endosomolytic Helical Polypeptide Hybrid Nanoparticles.
abstract: 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.
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University , 199 Ren'ai Road, Suzhou 215123, China.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Rujing
authors.initials: R
authors.lastname: Zhang
authors.affiliation: The Cyrus Tang Hematology Center, The Collaborative Innovation Center of Hematology, Soochow University , Suzhou 215123, China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The Cyrus Tang Hematology Center, The Collaborative Innovation Center of Hematology, Soochow University , Suzhou 215123, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Hematology-Oncology, Systems Immunobiology Laboratory, Children's Center for Cancer and Blood Diseases, Children's Hospital , Los Angeles, California 90027, United States.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign , 1304 West Green Street, Urbana, Illinois 61801, United States.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Applied Chemistry, School of Science, Xi'an Jiaotong University , Xi'an 710049, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University , 199 Ren'ai Road, Suzhou 215123, China.
authors.forename: Lichen
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D002460:Cell Line; D011992:Endosomes / Q000378:metabolism*; D006505:Hepatitis / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D010455:Peptides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha
keywords: TNF-α; anti-inflammation therapy; endosomal escape; helical polypeptide; membrane disruption; siRNA delivery