BCG‐Derived Outer Membrane Vesicles Induce TLR2‐Dependent Trained Immunity to Protect Against Polymicrobial Sepsis

作者：Yuan Gong, Wenyan Hao, Lingqi Xu, Yingyi Yang, Zhenzhen Dong, Peng Pan, Zhenjiang Bai, Jie Huang, Ke Yang, Zhu Jin, Rui Kang, Qiang Shan, J.H. Wang, J.H. Wang, Zijian Zhou, Daolin Tang, Jian Wang, Jian Wang, Huiting Zhou · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202504101 · 被引用次数：9 · 研究领域：Immune responses and vaccinations、Neonatal Respiratory Health Research、COVID-19 Impact on Reproduction

Trained immunity, an innate immune memory, has emerged as a promising strategy to enhance host defense against sepsis, a leading cause of mortality in critical care. While Bacillus Calmette-Guérin (BCG) is the most widely used vaccine for tuberculosis prevention, its broader use as an inducer of trained immunity is limited by adverse reactions. Here, it is reported that BCG-derived outer membrane vesicles (B-OMVs) effectively trigger trained immunity to protect against experimental polymicrobial sepsis. Comprehensive characterization and safety assessments confirmed that B-OMVs exhibited no significant toxicity or pathological effects, positioning them as a promising alternative to conventional BCG vaccines and E. coli-derived outer membrane vesicles (E-OMVs) in terms of both efficacy and safety. Mechanistically, B-OMVs enhanced trained immunity by promoting hematopoietic stem cell expansion and myelopoiesis via toll like receptor 2 (TLR2)-dependent activation of aerobic glycolysis and epigenetic reprogramming. This led to an amplified immune response and enhanced phagocytic activity in bone marrow-derived macrophages. Together, these findings establish B-OMVs as a novel immunomodulatory agent against sepsis-induced immune dysfunction, with translational potential.