Partially Epoxylated Lipidoids with Tertiary and Secondary Amines for Messenger RNA Transfection

Messenger RNA (mRNA) therapeutics have emerged as a powerful platform for disease prevention and treatment, a prominence amplified by the unprecedented success of SARS‐CoV‐2 vaccines. Among the available delivery vehicles, lipid nanoparticles (LNPs) are considered as the gold standard, with ionizable lipids—most often bearing tertiary amines—facilitating both nucleic acid encapsulation and endosomal release. In this study, we propose a versatile synthetic approach that enables the transformation of oligoamines into lipidoids, characterized by well‐defined distributions of tertiary and secondary amines through a controlled partial alkylation via epoxide ring‐opening reactions. The resulting partially epoxylated (pepo) lipidoids demonstrate dual utility: they serve as ionizable lipids in standard LNP formulations and even as single component transfecting agents in the absence of helper lipids. Five novel pepo‐lipidoids were synthesized, all of which exhibited superior mRNA delivery efficiency compared with fully epoxylated or unmodified counterparts. Notably, pepo‐triethylenetetramine (TETA), comprizing two secondary and two tertiary amines, ranked among the most potent candidates across both LNP‐based and single component transfections. Collectively, the results indicate the potential of engineering ionizable lipids with different types of protonatable nitrogens and position pepo‐lipidoids as a promising and adaptable class of materials for advancing mRNA delivery technologies.