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

Abstract 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.