Lipid nanoparticles carrying neutrophil extracellular trap inhibitors specifically target lung neutrophils and prevent COVID-19-associated lung injury in mice 9303

Abstract Description Although COVID-19 vaccination significantly reduces morbidity and mortality, and most individuals recover from acute SARS-CoV-2 infection, a substantial number continue to suffer from post-acute sequelae of COVID-19 (PASC). Currently, there are no efficient treatment options for COVID-19-related lung injury, and there is a critical need to identify therapeutic targets for PASC. In this study, we designed a lipid nanoparticle (LNP) platform to deliver two established neutrophil extracellular trap (NET) inhibitors, DNase I and Sivelestat, referred to as DPNLNPs, specifically to lung neutrophils. The LNP formulation was optimized with a cationic lipid for lung-specific delivery, and Ly6G antibodies were conjugated to the LNP surface for targeted neutrophil delivery. In vitro and in vivo experiments demonstrated that DPNLNPs preferentially accumulated in lung neutrophils and efficiently degraded NETs at much lower doses compared to free drugs. Administration of DPNLNPs in K18-hACE2 mice significantly inhibited SARS-CoV-2-induced NETs, which correlated with reduced inflammation and lung injury. Importantly, DPNLNP treatment during the symptomatic phase improved the survival outcomes of infected mice. Together, this study serves as proof-of-concept for adapting the LNP platform to deliver NET-targeted drugs to lung neutrophils. This preclinical evaluation highlights the potential of targeting neutrophils as an alternative strategy to reduce inflammation and fibrosis in COVID-19. Funding Sources This work was supported by KHIDI (RS-2023-00266015), NIH (R21AI140248), NIH/NIMHD (U54MD007601), Victoria S. And Bradley L. Geist Foundation, and Hawaii, Hawaii Community Foundation (MedRes_2024_00006576). Topic Categories Immune Mechanisms of Human Disease (HUM)