Intracellular delivery of nuclear localization sequence peptide mitigates COVID-19 by inhibiting nuclear transport of inflammation-associated transcription factors

Abstract

The novel coronavirus SARS-CoV-2, responsible for COVID-19, can trigger dysregulated immune responses known as cytokine release syndrome (CRS), leading to severe organ dysfunction and respiratory distress. Our study focuses on developing an improved cell-permeable nuclear import inhibitor, iCP-NI, capable of blocking the nuclear transport of inflammation-associated transcription factors (IATFs), specifically nuclear factor kappa B (NF-κB). By fusing advanced macromolecule transduction domains (aMTD) and nuclear localization sequences (NLS) from human NF-κB, iCP-NI selectively interacts with importin α5, effectively reducing the expression of pro-inflammatory cytokines. In mouse models with SARS-CoV-2-induced pneumonitis, iCP-NI treatment demonstrated a significant decrease in mortality rates by suppressing pro-inflammatory cytokine production and immune cell infiltration in the lungs. Similarly, in hamsters infected with SARS-CoV-2, iCP-NI effectively protected the lung from inflammatory damage by reducing TNF-α, IL-6, and IL-17 levels. These promising results highlight iCP-NI's potential as a therapeutic approach for COVID-19-related lung complications and other inflammatory lung diseases.