Ferritin Nanocage‐Based Methyltransferase SETD6 for COVID‐19 Therapy

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.