From a single library of siloxane-based lipidoids, siloxane-incorporated lipid nanoparticles (SiLNPs) involving minor alterations in lipid chemistry yield tissue-specific mRNA delivery to the liver, lung, or spleen. Upon enhanced intracellular delivery, these SiLNPs show clinical promise for protein replacement therapies, regenerative medicine, and CRISPR–Cas-based gene editing applications.