Lung-targeting immunomodulatory mRNA-lipid nanoparticle system

About This Grant

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI), characterized by uncontrolled inflammation, excessive pro-inflammatory cytokine expression, neutrophil infiltration, and damage to the alveolar-capillary barrier. Among the causes of ARDS, sepsis is the most prevalent, accounting for 32% of cases. Current management primarily relies on protective mechanical ventilation and supportive critical care. Despite advances, ARDS remains a leading cause of mortality, underscoring the urgent need for effective therapeutic interventions. Corticosteroids are widely used but are often accompanied by significant adverse effects. Alternative approaches have been explored, with IL-10 standing out as a potent pleiotropic cytokine that plays a critical role in modulating inflammation and maintaining immune homeostasis. IL -10 effectively suppresses LPS- and bacteria-induced pro-inflammatory cytokines. It showed promising results in ALI/ARDS treatment. However, its clinical translation has been hindered by suboptimal pharmacokinetics, instability, and non-specific distribution. To address these challenges, we propose developing a lung-targeted IL-10 mRNA therapy using our novel lung-targeting sulfonium lipid nanoparticle (sLNP) technology. Our hypothesis is that delivering IL-10 mRNA specifically to the lungs and inducing its expression at the injury site will enhance therapeutic efficacy while minimizing the risk of systemic side effects. Our pilot studies have demonstrated the efficacy and safety of IL-10 mRNA/sLNP in treating ALI/ARDS in mouse models. In this project, we aim to evaluate the safety, tissue distribution, and therapeutic potential of IL-10 mRNA/sLNP in a more clinically relevant swine model of sepsis-induced ARDS. The success of this study could transform ALI/ARDS management and pave the way for future innovations in targeted mRNA therapeutics for respiratory care.