Glibenclamide-encapsulated Liposomes alleviate LPS-induced Inflammatory Cascade through NLRP3 inhibition in macrophages

Abstract Inflammation is a vital immune response for survival during infection and tissue damage. It is critical in maintaining normal tissue homeostasis by orchestrating appropriate inflammatory mediators. Macrophages, integral to innate immunity, respond to lipopolysaccharide (LPS) present in gram-negative bacteria by releasing inflammatory cytokines. Utilizing nanotechnology for drug delivery have been proven with enhanced therapeutic approaches by targeting the suppression of inflammatory mediators and cytokines. Recent studies have provided insights into the role of inflammasomes in intracellular processes linked to inflammation. Glibenclamide (GLB), a sulfonylurea used in type 2 diabetes treatment, has emerged as a potent inhibitor of the NLRP3 inflammasome, showing promise in alleviating inflammation-associated injuries. To overcome the limitations of GLB, such as low aqueous solubility and high permeability, in this study, methyl-PEG-DSPE lipids were used to develop GLB-loaded nanoliposomes. The size of blank liposome was measured to be 120 nm. Anionic GLB-loaded liposomes, sized 146 nm with spherical morphology, effectively suppressed the expression of NLRP3 mediators (caspase-1, ASC, IL-1B, and IL-18) and various reactive oxygen species mediators compared to free GLB, reducing LPS-induced inflammatory responses in RAW264.7 macrophages. This suggests the potential of GLB-loaded liposomes as a therapeutic agent for inflammation-related disorders, warranting further in-vivo investigation.