Disulfiram-loaded lactoferrin nanoparticles for treating inflammatory diseases

An-te Ou1,2,3, Jia-xin Zhang1,4, Yue-fei Fang1,5, Rong Wang1,6, Xue-ping Tang1,5, Peng-fei Zhao1,7, Yu-ge Zhao8, Meng Zhang9, Yong-zhuo Huang1,1,2,3
1 .NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Zhongshan Institute for Drug Discovery, SIMM, CAS, Zhongshan 528437, China
4 Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
5 Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou 501450, China
6 Nanchang University College of Pharmacy, Nanchang 330006, China
7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
8 Tongji University School of Medicine, Shanghai 200092, China
9 Department of Pharmacy, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Correspondence to: Yong-zhuo Huang:,
DOI: 10.1038/s41401-021-00770-w
Received: 21 June 2021
Accepted: 22 August 2021
Advance online: 24 September 2021


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.
Keywords: disulfiram; lactoferrin; macrophage-targeting delivery; sepsis; ulcerative colitis; pyroptosis; inflammation

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