Ferritin Nanocage‐Based Methyltransferase SETD6 for COVID‐19 Therapy

Abstract

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.

Nanodiamond as a Cytokine Sponge in Infectious Diseases

“…CLP is a polymicrobial septic model and displays systemic inflammation and excessive production of cytokines in C57BL/6N mice ( Seemann et al, 2017 ). It is worth noting that the CLP model shares the common signaling pathways of sterol regulatory element-binding protein 2 (SREBP2) and nuclear factor κB (NF-κB) with COVID-19, sepsis, and pneumonia for the progression of the CRS ( Lee et al, 2020b ; Kim et al, 2020 ; Park et al, 2020 ). Briefly, a 2-cm midline incision was made to expose the cecum and adjoining intestine.…”

An Analysis in Identifying the Mechanism of Action of the Alkaloids Found in Berberis vulgaris on the Treatment and Prevention of SARS-CoV-2

“…37 In SARS-CoV-2 infection, SETD6 expression is downregulated. 38 Another methyltransferase SETDB1 has reduced levels of expression in children that develop more severe symptoms during infection with SARS-CoV-2 so it is presumed that increasing the levels would be protective. 39 Berberine is said to increase the expression of SETDB1.…”

Nano-engineered tools in the diagnosis, therapeutics, prevention, and mitigation of SARS-CoV-2

“…SET-domain containing 6 (SETD6) is known to inhibit viral infection mediated inflammation, but its use is restricted owing to the short half-life and poor intracellular delivery. In 2020, Kim et al [ 115 ] developed ferritin based nanocages for delivery of methyltransferase SETD6 for COVID-19 therapy. However, the toxicity assessment of nanocages must be considered before their use.…”