AbstractIonizable lipid‐based nanoparticles (LNPs) are the most advanced non‐viral drug delivery systems for RNA therapeutics and vaccines. However, cell type‐specific, extrahepatic mRNA delivery is still a major hurdle, hampering the development of novel therapeutic modalities. Herein, a novel ionizable lipid library is synthesized by modifying hydrophobic tail chains and linkers. Combined with other helper lipids and utilizing a microfluidic mixing approach, stable LNPs are formed. Using Luciferase‐mRNA, mCherry mRNA, and Cre mRNA together with a TdTomato animal model, superior lipids forming LNPs for potent cell‐type specific mRNA delivery are identified. In vitro assays concluded that combining branched ester tail chains with hydroxylamine linker negatively affects mRNA delivery efficiency. In vivo studies identify Lipid 23 as a liver‐trophic, superior mRNA delivery lipid and Lipid 16 as a potent cell type‐specific ionizable lipid for the CD11bhimacrophage population without an additional targeting moiety. Finally, in vivo mRNA delivery efficiency and toxicity of these LNPs are compared with SM‐102‐based LNP (Moderna's LNP formulation) and are shown to be cell‐specific compared to SM‐102‐based LNPs. Overall, this study suggests that a structural combination of tail and linker can drive a novel functionality of LNPs in vivo.