Lipid nanoparticles (LNPs) are clinically advanced delivery systems for RNA. The extensively developed structure of ionizable lipids greatly contributes to the functional delivery of mRNA. However, endosomal escape is one of the severe biological barriers that continue to render this process inefficient (e.g., less than 10%). Although LNPs contain phospholipids, their role is poorly understood, and there have been few attempts to perform the chemical engineering required to improve their functionality. Herein, a cubic phase-inducible fusogenic zwitterionic phospholipid derived from 1,2-dioleoyl-3-sn-glycero-phosphoethanolamine (DOPE), DOPE-Cx is described, that is designed to correct this problem. The orientation of a zwitterionic head group of DOPE is engineered by attaching a series of hydrophobic moieties for zwitterionic intermolecular interaction with the head structure of phosphatidylcholine (PC), and this is followed by a lipid-phase transition into non-lamellar phases to facilitate membrane fusion-mediated endosomal escape. A structure-activity relationship study reveals that DOPE-Cx lipids with small hydrophobic chains induce cubic phases instead of a hexagonal phase when mixed with PC, which enhances the functional delivery of mRNA in the liver as opposed to the action of the typically utilized and naturally occurring phospholipids. Engineered functionalized phospholipids will be of great value for the therapeutic applications of mRNAs.