Intracellular carbon monoxide release unveils selective antibacterial effects

Carbon monoxide (CO) is recognized as a diffusible and biologically membrane-permeable gasotransmitter. However, the question of whether extracellular and intracellular CO delivery would yield similar or distinct biological functions remains unresolved. In this study, utilizing nonmetallic CO-releasing micelles as a platform for localized CO delivery, we present evidence suggesting that selective antibacterial effects against Staphylococcus aureus (S. aureus) are exclusively evident upon intracellular CO release, even in cases of extracellular release with higher CO concentrations showing no comparable effect. To substantiate this assertion, we systematically design micellar nanoparticles with varying sizes, monomer sequences, and shell compositions. Among these variants, only the micelles taken up by S. aureus and capable of intracellular CO release exhibit efficient bacteria-killing properties. We further demonstrate that the selective bactericidal effect is closely linked to the production of hydroxyl radicals after intracellular CO release. Additionally, intracellular CO release proves to be an efficient treatment for S. aureus-induced skin abscesses without the need for additional antibiotics, showcasing synergistic antibacterial and anti-inflammatory effects. These findings underscore the pivotal role of the spatial location of CO release, significantly enhancing our understanding of the pathophysiological functions of gasotransmitters.