Abstract
Acute respiratory distress syndrome (ARDS), caused by widespread endothelial barrier disruption and uncontrolled cytokine storm, is the major feared complication of pandemic influenza and COVID-19. Currently, there are few pharmacological treatments that directly target ARDS. We have previously discovered that reduction of Krüppel-like Factor 2 (KLF2, a transcription factor) in inflamed endothelium leads to ARDS induced by LPS, influenza, and high-tidal volume ventilation. Recently, we detected a significant reduction of KLF2 in lung autopsies from COVID-19 patients and demonstrated the anti-viral function of endothelial KLF2. Here, we devised a VCAM1-targeting nanomedicine strategy to restore KLF2 in inflamed endothelial cells. We engineered a rationally designed liposome which possesses potent mRNA delivery and transfection capacity. This VCAM1-targeting liposome selectively delivered functional KLF2 mRNA to inflamed vascular endothelium and significantly reduced mouse ARDS induced by influenza virus H1N1 and SARS-CoV-2, by calming local cytokine storm and promoting endothelium health. Moreover, we demonstrated that this targeted liposome serves as a broad platform to effectively deliver various mRNA molecules to targeted tissues of interest by displaying different targeting motifs. Our results demonstrate that this KLF2 mRNA encapsulated, VCAM1-targeting liposome is a promising mRNA therapeutic strategy to treat ARDS and vascular diseases.
Published Version
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