SRP485906 PRJNA1068992 Red blood cell DNA capture and delivery during polymicrobial sepsis. Red blood cells (RBCs) express TLR9 and detect excess DNA leading to RBC clearance and innate immune activation. Whether RBCs detect microbial DNA during infection is unknown. We show that RBCs acquire microbial DNA during human and murine sepsis contributing to host inflammatory responses. 16S sequencing of RBC-bound DNA revealed distinct microbial DNA communities and RBC-bound DNA composition correlated with plasma IL-6 in patients with sepsis. These findings unveil RBCs as overlooked reservoirs of microbial DNA capable of influencing inflammatory responses in sepsis.