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

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 Jung, Elie Zakhem, Stephen Lenzini, Jiwan Woo, Hongyoon Choi, Jeongbin Park, Seung-Yoon Park, Gi Beom Kim (), Gi-Hoon Nam () and In-San Kim ()
Additional contact information
Seohyun Kim: SHIFTBIO INC
Yoon Kyoung Kim: SHIFTBIO INC
Seonghyun Kim: SHIFTBIO INC
Yong-Soon Choi: SHIFTBIO INC
Inkyu Lee: SHIFTBIO INC
Hyemin Joo: SHIFTBIO INC
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
Jeongbin Park: Portrai, Inc
Seung-Yoon Park: Dongguk University
Gi Beom Kim: SHIFTBIO INC
Gi-Hoon Nam: SHIFTBIO INC
In-San Kim: Korea University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57133-w

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