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Background <p>Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, with the gastrointestinal tract being a primary target organ. Dysregulated innate immune activation, particularly within intestinal macrophages, is increasingly recognized as a key contributor to GVHD pathogenesis; however, strategies for achieving localized and controllable immunomodulation remain limited.</p> Methods <p>Single-cell transcriptomic analyses were performed to characterize macrophage-associated inflammatory programs in intestinal tissues during GVHD. A programmable living therapeutic platform was engineered using Escherichia coli Nissle 1917 to secrete outer membrane vesicles (OMVs) encapsulating BigLEN, a peptide inhibitor of NLRP3 inflammasome activation. Following oral administration, OMV-mediated delivery, inflammasome-associated signaling, and therapeutic efficacy were evaluated using in vitro macrophage assays and multiple murine GVHD models, including a graft-versus-leukemia (GVL) setting.</p> Results <p>Single-cell transcriptomic analysis of intestinal biopsies revealed a marked enrichment of inflammasome and pyroptosis-associated transcriptional programs in macrophages during GVHD. To locally modulate this inflammatory axis, we engineered Escherichia coli Nissle 1917 to secrete outer membrane vesicles (OMVs) encapsulating BigLEN, a peptide inhibitor of NLRP3 inflammasome activation. Following oral administration, engineered OMVs enabled effective delivery of BigLEN to lamina propria macrophages, resulting in attenuation of inflammasome activation and associated pyroptosis-related inflammatory responses. In multiple murine GVHD models, this in situ immunomodulatory strategy significantly alleviated intestinal pathology, reduced systemic inflammatory cytokine production, and improved survival. Importantly, anti-leukemia activity was preserved in a graft-versus-leukemia (GVL) setting.</p> Conclusion <p>This study demonstrates the feasibility of a programmable, OMV-based living therapeutic platform for localized control of macrophage inflammasome activity in the gastrointestinal tract. This strategy achieves potent, local control of GVHD without overt impairment of graft-versus-leukemia (GVL) activity, and presents a novel targeted paradigm for treating gastrointestinal inflammatory disorders.</p> Graphical Abstract <p></p>

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A living therapeutic platform for localized in situ modulation of macrophage pyroptosis ameliorates GVHD while preserving GVL

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Zhuo Wan,
  • Zhenyu Xu,
  • Xuanting Liang,
  • Yueru Ji,
  • Jiayue Xi,
  • Zhuoyue Shi,
  • Yufei Hou,
  • Xueqian Yan,
  • Nian Li,
  • Li Liu,
  • Chaojun Song,
  • Li Fan,
  • Weiwei Qin

摘要

Background

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation, with the gastrointestinal tract being a primary target organ. Dysregulated innate immune activation, particularly within intestinal macrophages, is increasingly recognized as a key contributor to GVHD pathogenesis; however, strategies for achieving localized and controllable immunomodulation remain limited.

Methods

Single-cell transcriptomic analyses were performed to characterize macrophage-associated inflammatory programs in intestinal tissues during GVHD. A programmable living therapeutic platform was engineered using Escherichia coli Nissle 1917 to secrete outer membrane vesicles (OMVs) encapsulating BigLEN, a peptide inhibitor of NLRP3 inflammasome activation. Following oral administration, OMV-mediated delivery, inflammasome-associated signaling, and therapeutic efficacy were evaluated using in vitro macrophage assays and multiple murine GVHD models, including a graft-versus-leukemia (GVL) setting.

Results

Single-cell transcriptomic analysis of intestinal biopsies revealed a marked enrichment of inflammasome and pyroptosis-associated transcriptional programs in macrophages during GVHD. To locally modulate this inflammatory axis, we engineered Escherichia coli Nissle 1917 to secrete outer membrane vesicles (OMVs) encapsulating BigLEN, a peptide inhibitor of NLRP3 inflammasome activation. Following oral administration, engineered OMVs enabled effective delivery of BigLEN to lamina propria macrophages, resulting in attenuation of inflammasome activation and associated pyroptosis-related inflammatory responses. In multiple murine GVHD models, this in situ immunomodulatory strategy significantly alleviated intestinal pathology, reduced systemic inflammatory cytokine production, and improved survival. Importantly, anti-leukemia activity was preserved in a graft-versus-leukemia (GVL) setting.

Conclusion

This study demonstrates the feasibility of a programmable, OMV-based living therapeutic platform for localized control of macrophage inflammasome activity in the gastrointestinal tract. This strategy achieves potent, local control of GVHD without overt impairment of graft-versus-leukemia (GVL) activity, and presents a novel targeted paradigm for treating gastrointestinal inflammatory disorders.

Graphical Abstract