IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-51571-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51571-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-51571-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    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. "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.
    3. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Man Wu & Pok Man Hau & Linxian Li & Chi Man Tsang & Yike Yang & Aziz Taghbalout & Grace Tin-Yun Chung & Shin Yee Hui & Wing Chung Tang & Nathaniel Jillette & Jacqueline Jufen Zhu & Horace Hok Yeung Le, 2024. "Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Kai Liu & Ralf Nilsson & Elisa Lázaro-Ibáñez & Hanna Duàn & Tasso Miliotis & Marie Strimfors & Michael Lerche & Ana Rita Salgado Ribeiro & Johan Ulander & Daniel Lindén & Anna Salvati & Alan Sabirsh, 2023. "Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Roy Pattipeiluhu & Ye Zeng & Marco M.R.M. Hendrix & Ilja K. Voets & Alexander Kros & Thomas H. Sharp, 2024. "Liquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Kexin Su & Lu Shi & Tao Sheng & Xinxin Yan & Lixin Lin & Chaoyang Meng & Shiqi Wu & Yuxuan Chen & Yao Zhang & Chaorong Wang & Zichuan Wang & Junjie Qiu & Jiahui Zhao & Tengfei Xu & Yuan Ping & Zhen Gu, 2024. "Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Soeun Kang & Maciek R. Antoniewicz & Nissim Hay, 2024. "Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    6. Meirion Raymant & Yuliana Astuti & Laura Alvaro-Espinosa & Daniel Green & Valeria Quaranta & Gaia Bellomo & Mark Glenn & Vatshala Chandran-Gorner & Daniel H. Palmer & Christopher Halloran & Paula Ghan, 2024. "Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    7. Sonal Sinha & Satoka Aizawa & Yasuhiro Nakano & Alexander Rialdi & Hye Yeon Choi & Rajan Shrestha & Stephanie Q. Pan & Yibu Chen & Meng Li & Audrey Kapelanski-Lamoureux & Gregory Yochum & Linda Sher &, 2023. "Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51571-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.