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Pediatric Acute Respiratory Distress Syndrome (PARDS) is an urgent public health concern accounting for high mortality and long\u2010term morbidity due to severe damage to lung endothelial cells (ECs). Advanced target\u2010specific 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\u2010based Lung Endothelial Drug Delivery (LEDD) system to deliver hydrophobic small\u2010molecule compounds specifically to lung ECs but not to other cells or organs. Based on single\u2010cell 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\u2010activating compound, TanFe[F], which prevents FOXF1 protein degradation. LEDD\u2010TanFe[F] treatment increased FOXF1 protein and its activity in lung ECs in vitro and in vivo. LEDD\u2010TanFe[F] treatment was non\u2010toxic, well\u2010tolerated, and improved mice survival in the PARDS model. LEDD\u2010TanFe[F] reduced endothelial permeability, improved vascular repair, and alveolarization in injured neonatal lungs. LEDD\u2010supported drug delivery precisely to lung ECs is a promising therapeutic approach in PARDS.<\/jats:p>","DOI":"10.1002\/advs.78292","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:58:35Z","timestamp":1792036715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development of Versatile Nanoparticle System for Efficient Drug Delivery into Pulmonary Endothelium"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3488-0128","authenticated-orcid":false,"given":"Afzaal N.","family":"Mohammed","sequence":"first","affiliation":[{"name":"Phoenix Children's Research Institute, Department of Child Health University of Arizona College of Medicine\u2010Phoenix  Phoenix 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