Long-acting nanoparticulate DNase-1 for effective suppression of SARS-CoV-2-mediated neutrophil activities and cytokine storm

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus not previously identified in humans. Globally, the number of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) have risen dramatically. Currently, there are no FDA-approved antiviral drugs and there is an urgency to develop treatment strategies that can effectively suppress SARS-CoV-2-mediated cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. As symptoms progress in patients with SARS-CoV-2 sepsis, elevated amounts of cell-free DNA (cfDNA) are produced, which in turn induce multiple organ failure in these patients. Furthermore, plasma levels of DNase-1 are markedly reduced in SARS-CoV-2 sepsis patients. In this study, we generated recombinant DNase-1-coated polydopamine-poly(ethylene glycol) nanoparticulates (named long-acting DNase-1), and hypothesized that exogenous administration of long-acting DNase-1 may suppress SARS-CoV-2-mediated neutrophil activities and the cytokine storm. Our findings suggest that exogenously administered long-acting nanoparticulate DNase-1 can effectively reduce cfDNA levels and neutrophil activities and may be used as a potential therapeutic intervention for life-threatening SARS-CoV-2-mediated illnesses.

Role of biomaterials in the diagnosis, prevention, treatment, and study of corona virus disease 2019 (COVID-19)

“…6). The results of this study revealed an improved survival in sepsis mouse model because of inhibited NETosis factors [224].…”

“…The surface of the PLGA nanoparticles was coated with polydopamine to immobilize DNase-1. Reproduced from[224], with permission from Elsevier…”

Epigenetic mechanisms influencing COVID-19

“…Interaction between the viral spike (S) protein on the surface of the virus and the host receptor angiotensin-converting enzyme 2 (ACE2) on the surface of the target cell begins the process of viral entry inside host. ACE2 is a type I membrane receptor located across several cell types including endothelial cells of blood vessels, type II alveolar cells, small intestine enterocytes, and arterial smooth muscle cells of cerebral cortex, brainstem, and many organs (J. M. Kim et al, 2020). The S1 subunit of S contains a receptor binding domain (RBD) which binds to ACE2 6 for entry, and the binding is significantly enhanced by a single N501T mutation of ACE2, which indicates that screening for this mutation in populations can possibly determine proclivity to COVID-19 (Wan, Shang, Graham, Baric, & Li, 2020).…”

“…Further, symptoms of sepsis like cytokine storm, organ damage, increase of NETs in organs and circulation are reflected in COVID-19 where increased circulating neutrophil levels predict a worse outcome (T. Chen et al, 2020;Guan et al, 2020;Veras et al, 2020). Moreover, Cit-histone H3 levels are increased in the plasma samples of COVID-19 patients with sepsis (Lee et al, 2020).…”

SARS-CoV-2 infection: Understanding the immune system abnormalities to get an adequate diagnosis

“…In this regard, it has been proposed that the exogenous administration of recombinant DNase-1-coated nanoparticles or melanin-like nanospheres reduces ecDNA levels, neutrophil counts, and NETosis, ultimately modulating inflammation and lowering mortality [38,39].…”