Developing Highly Effective Nanoparticle mRNA Therapeutic for Pediatric Acute Respiratory Distress Syndrome.

Abstract

Sepsis-induced pediatric acute lung injury (ALI) and pediatric acute respiratory distress syndrome (PARDS) are life-threatening conditions with high mortality rates and no current cure. Most ALI/ARDS studies focus on adults, albeit the pediatric population has unique challenges often underrepresented. ALI/PARDS severely impacts pulmonary endothelial cells (ECs), causing endothelial dysfunction and vascular leakage. FOXF1 is a transcription factor critical for lung repair after injury, representing a viable target for ALI/PARDS. This study developed and tested a novel nanoparticle system for precise delivery of FOXF1 mRNA into lung ECs to reduce endothelial damage and improve lung function in mouse model of PARDS. Systemic inflammatory response was induced in neonatal mice after intraperitoneal administration of lipopolysaccharide (LPS). Specifically designed nanoparticles (NP) were used to intravenously deliver stabilized FOXF1 mRNA (FOXF1 NP) after LPS injury to restore FOXF1 expression in injured lung endothelial cells. FOXF1 NP selectively targeted pulmonary ECs without affecting other cell types or organs. FOXF1 NP treatment reduced vascular leakage, enhanced endothelial barrier function, and improved survival of neonatal mice after injury. FOXF1 NP decreased EC apoptosis by restoring the expression of BCL2, an anti-apoptotic FOXF1 target gene. Nanoparticle-based rescue of lung ECs has promise for future treatments of human ALI/PARDS.