This study presents a high-throughput barcoding screening system to identify cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. The authors synthesized 180 cationic, degradable lipids and screened them in vitro. Using barcoding technology, they quantified the delivery of DNA barcodes in vivo, identifying 96 promising lipid nanoparticles (LNPs). The top-performing LNP, LNP-CAD9, was found to preferentially deliver mRNA to the lungs, with ~90% of luciferase expression observed in the lungs. This LNP also demonstrated therapeutic potential in an antiangiogenic cancer therapy model, outperforming a gold-standard lung-tropic MC3/DOTAP LNP system. The study highlights the effectiveness of high-throughput barcoding technology in identifying structurally distinct nanoparticles for extrahepatic mRNA delivery to the lungs, with potential applications in protein replacement, vaccination, and gene editing.This study presents a high-throughput barcoding screening system to identify cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. The authors synthesized 180 cationic, degradable lipids and screened them in vitro. Using barcoding technology, they quantified the delivery of DNA barcodes in vivo, identifying 96 promising lipid nanoparticles (LNPs). The top-performing LNP, LNP-CAD9, was found to preferentially deliver mRNA to the lungs, with ~90% of luciferase expression observed in the lungs. This LNP also demonstrated therapeutic potential in an antiangiogenic cancer therapy model, outperforming a gold-standard lung-tropic MC3/DOTAP LNP system. The study highlights the effectiveness of high-throughput barcoding technology in identifying structurally distinct nanoparticles for extrahepatic mRNA delivery to the lungs, with potential applications in protein replacement, vaccination, and gene editing.