Therapeutic potential of DNases in immunothrombosis: promising succor or uncertain future?

Sepsis, a life-threatening condition characterized by systemic inflammation and multiorgan dysfunction, is closely associated with the excessive formation of neutrophil extracellular traps (NETs) and the release of cell-free DNA. Both play a central role in sepsis progression, acting as major contributors to immunothrombosis and associated complications. Endogenous DNases play a pivotal role in degrading NETs and cell-free DNA, yet their activity is often dysregulated during thrombotic disease. Although exogenous DNase1 administration has shown potential in reducing NET burden and mitigating the detrimental effects of immunothrombosis, its therapeutic efficacy upon intravenous administration remains uncertain. The development of engineered DNase formulations and combination therapies may further enhance its therapeutic effectiveness by modifying its pharmacodynamic properties and avoiding the adverse effects associated with NET degradation, respectively. Although NETs are well-established targets of DNase1, it remains uncertain whether the positive effects of DNase1 on immunothrombosis are exclusively related to it's targeting of NETs or if other components contributing to immunothrombosis are also affected. This review examines the endogenous regulation of NETs in circulation and the therapeutic potential of DNases in immunothrombosis, underscoring the necessity for further investigation to optimize their clinical application.