Development of Versatile Nanoparticle System for Efficient Drug Delivery into Pulmonary Endothelium

Drug delivery precisely to the pulmonary vasculature represents a formidable challenge. Pediatric Acute Respiratory Distress Syndrome (PARDS) is an urgent public health concern accounting for high mortality and long-term morbidity due to severe damage to lung endothelial cells (ECs). Advanced target-specific therapeutic interventions to protect lung vasculature in PARDS are in dire need. FOXF1 protein is a critical mediator of lung angiogenesis and vascular repair after injury. However, whether FOXF1 is a useful pharmacological target for PARDS is unknown. Herein, we developed a universal nanoparticle-based Lung Endothelial Drug Delivery (LEDD) system to deliver hydrophobic small-molecule compounds specifically to lung ECs but not to other cells or organs. Based on single-cell RNA sequencing, FOXF1 expression was decreased in lung ECs in the mouse PARDS model. We used LEDD nanoparticles to restore FOXF1 by delivering a novel FOXF1-activating compound, TanFe[F], which prevents FOXF1 protein degradation. LEDD-TanFe[F] treatment increased FOXF1 protein and its activity in lung ECs in vitro and in vivo. LEDD-TanFe[F] treatment was non-toxic, well-tolerated, and improved mice survival in the PARDS model. LEDD-TanFe[F] reduced endothelial permeability, improved vascular repair, and alveolarization in injured neonatal lungs. LEDD-supported drug delivery precisely to lung ECs is a promising therapeutic approach in PARDS.