Dual-mode action of scalable, high-quality engineered stem cell-derived SIRPα-extracellular vesicles for treating acute liver failure
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.
Authors
- Seung‐Yoon Park (ORCID: https://orcid.org/0000-0002-1772-2523)
- Yoon Kyoung Kim (ORCID: https://orcid.org/0000-0002-4812-1843)
- In‐San Kim (ORCID: https://orcid.org/0000-0003-1714-4521)
- Jeongbin Park (ORCID: https://orcid.org/0000-0002-5073-3451)
- Seryoung Park (ORCID: https://orcid.org/0009-0003-0963-187X)
- Yoonjeong Choi (ORCID: https://orcid.org/0000-0003-3559-7233)
- Hyemin Joo (ORCID: https://orcid.org/0009-0006-0227-4269)
- Seonghyun Kim
- Jiwan Woo (ORCID: https://orcid.org/0000-0002-1823-5305)
- Gi‐Hoon Nam (ORCID: https://orcid.org/0000-0003-2115-3818)
- Hongyoon Choi (ORCID: https://orcid.org/0000-0002-8895-2449)
- Yong‐Soon Choi (ORCID: https://orcid.org/0009-0009-6272-9984)
- Stephen Lenzini (ORCID: https://orcid.org/0000-0002-2585-4817)
- Min Kyoung Jo (ORCID: https://orcid.org/0000-0002-6448-4038)
- Jaehyun Kim
- Elie Zakhem
- Gi Beom Kim
- Inkyu Lee (ORCID: https://orcid.org/0000-0002-8246-6415)
- Jae Woong Jung
- Seohyun Kim (ORCID: https://orcid.org/0000-0002-5349-1240)
- Minjeong Kwon (ORCID: https://orcid.org/0009-0002-1787-1892)
- Theresa D’Souza
Institutions
- Korea University (KR)
- Dongguk University (KR)
- Seoul National University Hospital (KR)
- Korea Research Institute of Chemical Technology (KR)
- Korea University (JP)
- Shift (United Kingdom) (GB)
- Korea Institute of Science and Technology (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-23
- DOI
- https://doi.org/10.1038/s41467-025-57133-w
- Citations
- 15
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 11.96