【摘 要】
：
Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction,which is often seen in serious Covid-19 patients.Disulfiram (DSF),an old drug that has been used to treat alcohol addiction for decades,has r
【机 构】
：
State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Scienc
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Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction,which is often seen in serious Covid-19 patients.Disulfiram (DSF),an old drug that has been used to treat alcohol addiction for decades,has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release.Therefore,DSF represents a promising therapeutic for the treatment of inflammatory disorders.Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses.In addition,LF has been well exploited as a drug nanocarrier and targeting ligands.In this study,we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF.DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages.Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis.In addition,this therapeutic strategy was also applied to treat ulcerative colitis (UC),and substantial treatment efficacy was achieved in a murine colitis model.The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC.As macrophage pyroptosis plays a pivotal role in inflammation,this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.
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