Systemically administered lipid nanoparticles (LNPs) predominantly target the liver, limiting their use for extrahepatic applications. Here, we introduce cyclam-based ionizable lipids that confer selective lung tropism after intravenous dosing. A ten-member library spanning three linker chemotypes and varied hydrophobic tails produced LNPs that consistently delivered mRNA to the lung. Lipids with aromatic linkers yielded compact nanoparticles (50–80 nm), with high encapsulation and RNA recovery, and outperformed DLin-MC3-DMA in vitro and in vivo. In Ai9 reporter mice, two intravenous doses of Cre mRNA formulated with lead cyclam lipid achieved ~30% lung editing with minimal off-organ activity. Structure–property analyses showed that increasing lipophilicity and aromatic content correlated inversely with particle size and positively with encapsulation, establishing design rules for macrocycle-guided delivery. Cyclam-based ionizable lipids thus enable systemically administered, lung-selective expression and provide a versatile platform for mRNA and gene-editing therapies.