Lipopolysaccharide (LPS) activates the Toll-like receptor (TLR)-4 sensor on the cell membrane of macrophages, triggering myeloid differentiation primary response 88 (MYD88)-dependent and independent pathways and subsequent activation of the nuclear factor kappa B (NF-κB) or interferon regulatory factor (IRF) transcription factors.Gram-negative bacteria use outer membrane vesicles and toxin-mediated pathways to deliver LPS into macrophages, triggering inflammasome activation in mouse models of sepsis.The SARS-CoV-2 spike protein binds LPS, thereby activating the NF-κB pathway in human monocytes and in mice.Hepatocytes and lung epithelial cells secrete proteins high mobility group box 1 (HMGB1) and secretoglobin family 3A member 2 (SCGB3A2), along with extracellular vesicles derived from serum, to transport LPS into macrophages; this consequently activates caspase (CASP)-11/4/5-dependent inflammasomes.LPS delivery systems have a pivotal role in initiating non-canonical NOD-like receptor protein 3 (NLRP3) inflammasome activation, leading to the release of interleukin (IL)-1β and IL18, and contributing to lethal infection in mouse models. LPS, commonly known as endotoxin, is a complex molecule primarily found in the outer membrane of Gram-negative bacteria, and has a crucial role in triggering inflammatory responses. Recent studies have illuminated LPS delivery systems used by both pathogens and hosts, providing insights into host–pathogen interactions. Modulating these delivery pathways could help regulate immune responses, potentially leading to the development of new treatments for infectious diseases, sepsis, and other inflammatory conditions. Lipopolysaccharide (LPS), a key component of the outer membrane in Gram-negative bacteria (GNB), is widely recognized for its crucial role in mammalian innate immunity and its link to mortality in intensive care units. While its recognition via the Toll-like receptor (TLR)-4 receptor on cell membranes is well established, the activation of the cytosolic receptor caspase-11 by LPS is now known to lead to inflammasome activation and subsequent induction of pyroptosis. Nevertheless, a fundamental question persists regarding the mechanism by which LPS enters host cells. Recent investigations have identified at least four primary pathways that can facilitate this process: bacterial outer membrane vesicles (OMVs); the spike (S) protein of SARS-CoV-2; host-secreted proteins; and host extracellular vesicles (EVs). These delivery systems provide new avenues for therapeutic interventions against sepsis and infectious diseases. Lipopolysaccharide (LPS), a key component of the outer membrane in Gram-negative bacteria (GNB), is widely recognized for its crucial role in mammalian innate immunity and its link to mortality in intensive care units. While its recognition via the Toll-like receptor (TLR)-4 receptor on cell membranes is well established, the activation of the cytosolic receptor caspase-11 by LPS is now known to lead to inflammasome activation and subsequent induction of pyroptosis. Nevertheless, a fundamental question persists regarding the mechanism by which LPS enters host cells. Recent investigations have identified at least four primary pathways that can facilitate this process: bacterial outer membrane vesicles (OMVs); the spike (S) protein of SARS-CoV-2; host-secreted proteins; and host extracellular vesicles (EVs). These delivery systems provide new avenues for therapeutic interventions against sepsis and infectious diseases.