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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-02-23 DOI:10.1038/s41467-025-57133-w

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, In-San Kim

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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.

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可扩展的高质量工程干细胞衍生的sirp α-细胞外囊泡治疗急性肝衰竭的双模式作用

急性肝衰竭（ALF）是由肝细胞快速死亡和肝脏再生受损引起的一种危及生命的疾病。在这里，我们展示了通过可扩展的3D生物反应器工艺生产的表达信号调节蛋白α (SIRP-EVs)的细胞外囊泡，具有高产率和纯度，通过靶向受损细胞和促进组织修复显示出显著的治疗潜力。sirp - ev阻断CD47这一对坏死细胞至关重要的抑制信号，从而增强巨噬细胞介导的对死亡肝细胞的清除。它们还从间充质干细胞中运送再生货物，重新编程巨噬细胞以支持肝脏再生。在雄性动物模型中，sirp - ev显著降低肝损伤标志物，提高生存率，显示出其双重功能的治疗功效。通过将坏死坏死的解决与再生巨噬细胞重编程结合起来，sirp - ev代表了恢复肝功能的一个有前途的平台。这些发现支持了基于EV的体内巨噬细胞重编程治疗ALF和其他炎症驱动疾病的发展，为工程化EV治疗的临床应用铺平了道路。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.