BACKGROUND: New bio-mimetic approaches are needed to develop effective delivery systems for inflammation regulation in chronic diseases like ulcerative colitis, avoiding fast clearance by immune system. The cell membrane-coated nanoparticle with a therapeutic payload has been considered as a promising delivery system to address the requirement. METHODS: Here, Glibenclamide (GLY)-loaded PLGA nanoparticles (NPs) were constructed by a single emulsion procedure and camouflaged by a layer of monocyte membrane using the extrusion technique to fabricate bio-mimetic nanoghosts (NGs), followed by physiochemical and biological characterizations. RESULTS: Upon coating the NPs by the membrane, the hydrodynamic size and zeta potential of NGs was changed. The formation of the shell compartment with diameter of about 15.5nm around NP core was confirmed by TEM. The expression levels of NLRP3, IL-1β, IL-18, caspase-1, TNF-α and IL-6 were decreased upon the NGs treatment. The lower cellular internalization of the NGs exhibited potential for improved circulation stability against macrophage phagocytosis. Treatment of acetic acid-induced UC with NGs exhibited healing of the mucosal lining in the colon tissue. CONCLUSION: The monocyte membrane-coated NPs with a sulfonylurea derivatives payload can be considered as an excellent biologically inspired candidate for management of inflammatory diseases like UC via inflammation regulation.