Hong Nam Kima,b, Hee Ho Parkc, Wonhee Limd,e, Kyung Soo Hongf, June Hong Ahnf, Dong Hee Nag, In‐San Kimh,i, Jong Geol Jangf,*, Jong‐Sup Baej,*, Wonhwa Leek,*
aCenter for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
bDivision of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea
cDepartment of Biotechnology and Bioengineering, Kangwon National University, Chuncheon, Gangwon-do 24341, Republic of Korea
dRare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
eDepartment of Functional Genomics, University of Science and Technology, Daejeon 34141, Republic of Korea
fDivision of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu 42415, Republic of Korea
gCollege of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
hBiomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
iKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
jCollege of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea
kAging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
H.N.K., H.H.P., and W.L. contributed equally to this study.
*To whom correspondence should be addressed.
The transcription factor nuclear factor‐κB (NF‐κB) signaling is a mediator of viral infection‐mediated inflammation and SET‐domain containing 6 (SETD6) is known as a methyltransferase that suppresses the activity of NF‐κB signaling. However, the downside of the SETD6 is that it cannot be directly utilized as an inflammatory regulator due to the short half‐life and poor intracellular delivery. Here, a ferritin nanocage‐based delivery system is presented that can maintain the activity of SETD6 in vivo. According to the analysis of severe COVID‐19 patients’ peripheral blood mononuclear cells (PBMCs), the SETD6 expression is downregulated while that of NF‐κB is upregulated. By engineering the structure of ferritin, a protein scaffold is fabricated in which short ferritin is decorated with cell‐penetrating peptide and nuclear‐localizing TAT‐NBD peptide together with SETD6, termed TFS. The TFS enhances the SETD6 level and reduces the NF‐κB signaling in PBMCs of severe COVID‐19 patients and subsequently suppresses the cytokine storm. When the TFS is intravenously administered in the cytokine storm mouse model, the survival rate is rescued and the lung tissue damage and cytokine expression are also inhibited. These results indicate that the ferritin nanocage‐based peptide delivery system allows stable in vivo delivery and efficient suppression of NF‐κB signaling‐mediated inflammation.