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      Retinol-binding protein-hijacking nanopolyplex delivering siRNA to cytoplasm of hepatic stellate cell for liver fibrosis alleviation.

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          Abstract

          Activated hepatic stellate cell (aHSC) is mainly responsible for deposition of extracellular collagen matrix that causes liver fibrosis. Although several siRNAs adequately inhibited HSC activation in vitro, they were demonstrated poor RNAi efficiency in vivo. Developing HSC-targeting and cytoplasmic delivery nanocarrier is highly essential to acquire a desirable siRNA therapeutic index for anti-liver fibrosis. Here, we developed a unique crosslinking nanopolyplex (called T-C-siRNA) modified by vitamin A (VA) with the well-designed natures, including the negative charge, retinol-binding protein (RBP) hijacking, and cytoplasmic siRNA release in response to ROS and cis diol molecules. The nanopolyplex was given a yolk-shell-like shape, camouflage ability in blood, and HSC-targeting capability by hijacking the endogenous ligand RBP via surface VA. PDGFR-β siRNA (siPDGFR-β) supplied via T-C-siPDGFR-β nanopolyplex dramatically reduced HSC activation and its production of pro-fibrogenic proteins in vitro and in vivo. Furthermore, T-C-siPDGFR-β nanopolyplex effectively alleviated CCl4-induced liver injury, decreased hepatic collagen sediment, and recovered liver function in mice. This study provides a sophisticated method for HSC-targeting cytoplasmic RNA delivery using endogenous ligand hijacking and dual sensitivity of ROS and cis diol compounds.

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          Author and article information

          Journal
          Biomaterials
          Biomaterials
          Elsevier BV
          1878-5905
          0142-9612
          Aug 2023
          : 299
          Affiliations
          [1 ] Department of Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China. Electronic address: huangjsh55@mail.sysu.edu.cn.
          [2 ] College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
          [3 ] Department of Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China.
          [4 ] Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China; PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
          [5 ] PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
          [6 ] School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China. Electronic address: yyy@zcmu.edu.cn.
          [7 ] College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. Electronic address: wangy488@jnu.edu.cn.
          [8 ] Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. Electronic address: shuaixt@mail.sysu.edu.cn.
          Article
          S0142-9612(23)00142-4
          10.1016/j.biomaterials.2023.122134
          37167895
          c7efdde9-e0b0-4704-922a-489312317a67
          History

          RNA delivery,Liver fibrosis,Hepatic stellate cell,Biomimetic nanosystem,Stimulus-responsive copolymer

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