Inhibition of IL-1β release from macrophages targeted with necrosulfonamide-loaded porous nanoparticles

Inflammation is required for protective responses against pathogens and is thus essential for survival, but sustained inflammation can lead to diseases, such as atherosclerosis and cancer.Two important mediators of inflammation are the cytokines IL-1β and IL-18, which are produced by myeloid cells of the immune system, including macrophages.These cytokines are released into the extracellular space through pores formed in the plasma membrane by the oligomerized protein gasdermin D (GSDMD).Necrosulfonamide (NSA) was recently identified as an effective GSDMD inhibitor and represents a promising therapeutic agent in GSDMD-dependent inflammatory diseases.Here, we targeted NSA to both mouse and human macrophages by using three different types of porous nanoparticles (NP), i.e. mesoporous silica (MSN), porous crosslinked cyclodextrin carriers (CD-NP), and a mesoporous magnesiumphosphate carrier (MPC-NP), all displaying high loading capacities for this hydrophobic drug.Cellular uptake and intracellular NSA delivery were tracked in time-lapse experiments by live-cell, high-throughput fluorescence microscopy, demonstrating Cover