COVID-19 O-001 : Bioinspired DNase-I-coated Melanin-like Nanospheres for Modulation of Infection-associated NETosis Dysregulation

Background Infection by SARS-CoV-2 causes both uncontrolled inflammatory innate immune responses and impaired adaptive immune responses, leading to local and systemic tissue damage. The factor or process that initiates and propagates the cytokine storm that drives severe COVID-19 is unknown; however, a recent study has proposed that excessive neutrophil extracellular traps (NETs), a special type of neutrophil-specific programmed cell death, could be associated with poor outcomes in severe patients and may play a pivotal role in COVID-19 pathogenesis. We suggest that the dissolution of a basic constituent of NET structure―DNA ―using DNase-I may be appropriate for preventing NET-related pathogenesis in SARS-CoV-2 patients. Methods Whole blood samples were collected from patients after they were diagnosed with the SARS-CoV-2 infection at Yeungnam University Medical Center. Recombinant DNase-I was purchased from Roche (Basel, Switzerland). To demonstrate the effects of DNase-I on DNA degradation, we treated the plasma of severe COVID-19 patients with either free DNase-I or DNase-I-coated melanin-like nanospheres (DNase-I pMNSs). Results The Results (Figure 1) showed that both forms of DNase-I significantly reduced the eDNA levels, and that exposure of DNase-I to the plasma of severe COVID-19 patients increased the activity of DNase-I. We also observed markedly reduced NET levels, MPO activity, and NE levels in neutrophils of severe COVID-19 patients upon treatment with DNase-I pMNSs. The activity of NF-kB and secretion of cytokines IL-1b, IL-6, IFN-g, and TNF-a were slightly reduced upon treatment with free DNase-I, and were further drastically reduced upon treatment with DNase-I pMNSs. Conclusions We demonstrated that eDNA, a NETosis factor, is a potential target for the treatment of SARS-CoV-2-induced sepsis. DNase-I pMNSs are able to modulate COVID-19-associated NETosis dysregulation and prevent further progression of the disease. The DNase-I pMNSs have potential applications in the treatment of SARS-CoV-2-related illnesses and other beta-CoV-related diseases.