TTP-3 is an asymmetric Ugi-derived ionizable lipid developed specifically for pulmonary delivery of structured suppressor tRNA cargo. Its architecture combines a dimethylaminopropyl ionizable headgroup, two amide-containing linkages, and chemically distinct hydrophobic tails. Selected from a 1,000-member lipid library, TTP-3 showed the strongest suppressor-tRNA delivery in a cystic-fibrosis-relevant air–liquid interface model containing artificial mucus. An optimized formulation containing TTP-3, DOPE, β-sitosterol, and C14-PEG2000 produced approximately 38-fold higher functional pulmonary reporter expression than MC3 following intratracheal administration in mice. TTP-3 LNPs preferentially delivered tRNA to airway epithelial cells, including ciliated, club, ionocyte, and basal progenitor populations. When combined with chemically modified suppressor tRNAs, the platform restored CFTR expression and function in cellular, mouse, and patient-derived organoid models. TTP-3 remains a preclinical research lipid, and further optimization is required for aerosol delivery, repeat dosing, and clinical translation.
