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RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment

Author

Listed:
  • Xinzhu Shan

    (Peking University
    Peking University)

  • Zhiqiang Zhao

    (Peking University
    Peking University
    Shenyang Pharmaceutical University)

  • Pingping Lai

    (Peking University)

  • Yuxiu Liu

    (Chinese Institute for Brain Research)

  • Buyao Li

    (Peking University)

  • Yubin Ke

    (Chinese Academy of Science)

  • Hanqiu Jiang

    (Chinese Academy of Science)

  • Yilong Zhou

    (Tumor Hospital Affiliated to Nantong University)

  • Wenzhe Li

    (Peking University)

  • Qian Wang

    (Peking University)

  • Pengxia Qin

    (Peking University)

  • Yizhe Xue

    (Peking University)

  • Zihan Zhang

    (Peking University)

  • Chenlong Wei

    (Peking University)

  • Bin Ma

    (Peking University
    Peking University)

  • Wei Liu

    (Keymed Biosciences (Chengdu) Limited)

  • Cong Luo

    (Shenyang Pharmaceutical University)

  • Xueguang Lu

    (Chinese Academy of Sciences)

  • Jiaqi Lin

    (Dalian University of Technology)

  • Li Shu

    (Chinese Academy of Sciences)

  • Yin Jie

    (Chinese Institute for Brain Research)

  • Xunde Xian

    (Peking University)

  • Derfogail Delcassian

    (UC Berkeley)

  • Yifan Ge

    (Chinese Academy of Sciences)

  • Lei Miao

    (Peking University
    Peking University
    Peking University-Yunnan Baiyao International Medical Research Center)

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) poses challenges for targeted delivery and retention of therapeutic proteins due to excess extracellular matrix (ECM). Here we present a new approach to treat MASH, termed “Fibrosis overexpression and retention (FORT)”. In this strategy, we design (1) retinoid-derivative lipid nanoparticle (LNP) to enable enhanced mRNA overexpression in fibrotic regions, and (2) mRNA modifications which facilitate anchoring of therapeutic proteins in ECM. LNPs containing carboxyl-retinoids, rather than alcohol- or ester-retinoids, effectively deliver mRNA with over 10-fold enhancement of protein expression in fibrotic livers. The carboxyl-retinoid rearrangement on the LNP surface improves protein binding and membrane fusion. Therapeutic proteins are then engineered with an endogenous collagen-binding domain. These fusion proteins exhibit increased retention in fibrotic lesions and reduced systemic toxicity. In vivo, fibrosis-targeting LNPs encoding fusion proteins demonstrate superior therapeutic efficacy in three clinically relevant male-animal MASH models. This approach holds promise in fibrotic diseases unsuited for protein injection.

Suggested Citation

  • Xinzhu Shan & Zhiqiang Zhao & Pingping Lai & Yuxiu Liu & Buyao Li & Yubin Ke & Hanqiu Jiang & Yilong Zhou & Wenzhe Li & Qian Wang & Pengxia Qin & Yizhe Xue & Zihan Zhang & Chenlong Wei & Bin Ma & Wei , 2024. "RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51571-8
    DOI: 10.1038/s41467-024-51571-8
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    1. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Author Correction: Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    3. Aveline Filliol & Yoshinobu Saito & Ajay Nair & Dianne H. Dapito & Le-Xing Yu & Aashreya Ravichandra & Sonakshi Bhattacharjee & Silvia Affo & Naoto Fujiwara & Hua Su & Qiuyan Sun & Thomas M. Savage & , 2022. "Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis," Nature, Nature, vol. 610(7931), pages 356-365, October.
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