Bioinspired DNase‐I‐Coated Melanin‐Like Nanospheres for Modulation of Infection‐Associated NETosis Dysregulation

Abstract

The current outbreak of the beta-coronavirus (beta-Cov) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in December 2019. No specific antiviral treatments or vaccines are currently available. A recent study has reported that coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2 infection, is associated with neutrophil-specific plasma membrane rupture, and release excessive neutrophil extracellular traps (NETs) and extracellular DNAs (eDNAs). This mechanism involves the activation of NETosis, a neutrophil-specific programmed cell death, which is believed to play a crucial role in COVID-19 pathogenesis. Further progression of the disease can cause uncontrolled inflammation, leading to the initiation of cytokine storms, acute respiratory distress syndrome (ARDS), and sepsis. Herein, it is reported that DNase-I-coated melanin-like nanospheres (DNase-I pMNSs) mitigate sepsis-associated NETosis dysregulation, thereby preventing further progression of the disease. Recombinant DNase-I and poly(ethylene glycol) (PEG) are used as coatings to promote the lengthy circulation and dissolution of NET structure. The data indicate that the application of bioinspired DNase-I pMNSs reduce neutrophil counts and NETosis-related factors in the plasma of SARS-CoV-2 sepsis patients, alleviates systemic inflammation, and attenuates mortality in a septic mouse model. Altogether, the findings suggest that these nanoparticles have potential applications in the treatment of SARS-CoV-2-related illnesses and other beta-CoV-related diseases.

Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets

“…Concentrations of a range of NET-associated markers, including cell-free DNA (cfDNA), MPO/NE-DNA complexes and citrullinated histone H3 (CitH3), have all been shown to be significantly increased in the circulation and/or tracheal aspirates of patients with COVID-19 (26,46,65,66,105,134,(166)(167)(168)(169)(170). As expected for a respiratory infection, NET levels are significantly higher in tracheal aspirates, bronchiolar lavage and BALF samples when compared to plasma (65,66).…”

“…Responsible for the breakdown of 90% of circulating cfDNA, deoxyribonuclease-1 (DNase-1) is the predominant endonuclease in bodily fluids ( 252 ). Relative to HCs, patients with severe, but not mild, COVID-19 exhibit significantly reduced circulating levels of this endonuclease ( 166 ), whose plasma concentrations have also been shown to be significantly lower in COVID-19 non-survivors when compared to survivors ( 169 ). In terms of function, significantly impaired total DNase activity has been measured in serum samples acquired from COVID-19 patients with mild and severe disease ( 233 ).…”

Neutrophil Extracellular Traps: A Potential Therapeutic Target in MPO-ANCA Associated Vasculitis?

“…DNase I coated melanin-like nanospheres have been used successfully to control NET dysregulation in a model of sepsis ( 103 ). To circumvent the relative short half-life of DNase I in the circulation bare bioinspired melanin-like nanospheres (bMNSs) are coated with polydopamine which immobilizes DNase I on the surface of the bMNSs.…”

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

“…With both treatments, the authors noted significant decreases in extracellular DNA, NET percentage, myeloperoxidase activity, and NE, along with a significant increase in relative plasma DNase activity. Interestingly, treatment with DNase-I pMNSs was more effective than free DNase I at reducing cytokine secretion from neutrophils such as NF-κβ and TNF-α [ 138 ]. As a result of these beneficial effects, it is worth exploring the use of DNase-I nanotechnology in the setting of PDAC NETs.…”