ArticleJournal of nanobiotechnology2026
A living therapeutic platform for localized in situ modulation of macrophage pyroptosis ameliorates GVHD while preserving GVL.
Article in Journal of nanobiotechnology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundGraft-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.
methodsSingle-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.
resultsSingle-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.
conclusionThis 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.
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