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Dual-mode action of scalable, high-quality engineered stem cell-derived SIRPα-extracellular vesicles for treating acute liver failure

Author

Listed:
  • Seohyun Kim

    (SHIFTBIO INC)

  • Yoon Kyoung Kim

    (SHIFTBIO INC)

  • Seonghyun Kim

    (SHIFTBIO INC)

  • Yong-Soon Choi

    (SHIFTBIO INC)

  • Inkyu Lee

    (SHIFTBIO INC
    Korea University)

  • Hyemin Joo

    (SHIFTBIO INC
    Korea University)

  • Jaehyun Kim

    (SHIFTBIO INC)

  • Minjeong Kwon

    (Korea University College of Medicine)

  • Seryoung Park

    (Korea University College of Medicine)

  • Min Kyoung Jo

    (Korea University College of Medicine)

  • Yoonjeong Choi

    (SHIFTBIO INC)

  • Theresa D’Souza

    (RoosterBio, Inc)

  • Jae Woong Jung

    (RoosterBio, Inc)

  • Elie Zakhem

    (RoosterBio, Inc)

  • Stephen Lenzini

    (RoosterBio, Inc)

  • Jiwan Woo

    (Korea Institute of Science and Technology (KIST))

  • Hongyoon Choi

    (Seoul National University College of Medicine
    Portrai, Inc)

  • Jeongbin Park

    (Portrai, Inc)

  • Seung-Yoon Park

    (Dongguk University)

  • Gi Beom Kim

    (SHIFTBIO INC)

  • Gi-Hoon Nam

    (SHIFTBIO INC
    Korea University College of Medicine)

  • In-San Kim

    (Korea University
    Korea Institute of Science and Technology (KIST))

Abstract

Acute liver failure (ALF) is a life-threatening condition caused by rapid hepatocyte death and impaired liver regeneration. Here we show that extracellular vesicles engineered to express Signal Regulatory Protein Alpha (SIRP-EVs), produced via a scalable 3D bioreactor process with high yield and purity, exhibit significant therapeutic potential by targeting damaged cells and promoting tissue repair. SIRP-EVs block CD47, a crucial inhibitory signal on necroptotic cells, to enhance macrophage-mediated clearance of dying hepatocytes. They also deliver regenerative cargo from mesenchymal stem cells, reprogramming macrophages to support liver regeneration. In male animal models, SIRP-EVs significantly reduce liver injury markers and improve survival, demonstrating their dual-function therapeutic efficacy. By integrating the resolution of necroptosis with regenerative macrophage reprogramming, SIRP-EVs represent a promising platform for restoring liver function. These findings support the development of EV-based in vivo macrophage reprogramming therapies for ALF and other inflammation-driven diseases, paving the way for the clinical application of engineered EV therapeutics.

Suggested Citation

  • Seohyun Kim & Yoon Kyoung Kim & Seonghyun Kim & Yong-Soon Choi & Inkyu Lee & Hyemin Joo & Jaehyun Kim & Minjeong Kwon & Seryoung Park & Min Kyoung Jo & Yoonjeong Choi & Theresa D’Souza & Jae Woong Jun, 2025. "Dual-mode action of scalable, high-quality engineered stem cell-derived SIRPα-extracellular vesicles for treating acute liver failure," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57133-w
    DOI: 10.1038/s41467-025-57133-w
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    References listed on IDEAS

    as
    1. Ping An & Lin-Lin Wei & Shuangshuang Zhao & Deanna Y. Sverdlov & Kahini A. Vaid & Makoto Miyamoto & Kaori Kuramitsu & Michelle Lai & Yury V. Popov, 2020. "Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Gi-Hoon Nam & Eun Jung Lee & Yoon Kyoung Kim & Yeonsun Hong & Yoonjeong Choi & Myung-Jeom Ryu & Jiwan Woo & Yakdol Cho & Dong June Ahn & Yoosoo Yang & Ick-Chan Kwon & Seung-Yoon Park & In-San Kim, 2018. "Combined Rho-kinase inhibition and immunogenic cell death triggers and propagates immunity against cancer," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
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