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Cubic Phase-Inducible Zwitterionic Phospholipids Improve the Functional Delivery of mRNA
Kazuki Iwakawa1, Rikako Sato1, Mariko Konaka1
1Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 17, 2025
Summary
Researchers engineered a novel phospholipid, DOPE-Cx, to improve mRNA delivery by enhancing endosomal escape. This zwitterionic phospholipid facilitates lipid-phase transitions, significantly boosting functional mRNA delivery in the liver.
Area of Science:
- Biotechnology
- Materials Science
- Drug Delivery
Background:
- Lipid nanoparticles (LNPs) are advanced delivery systems for RNA therapeutics, primarily mRNA.
- Ionizable lipids are crucial for LNP functionality, but endosomal escape remains a significant barrier, limiting delivery efficiency to below 10%.
- The role of phospholipids within LNPs is poorly understood, with limited chemical engineering efforts to enhance their function.
Purpose of the Study:
- To engineer a novel phospholipid, DOPE-Cx, designed to overcome the endosomal escape barrier in mRNA delivery.
- To investigate the structure-activity relationship of engineered phospholipids for improved LNP functionality.
- To enhance the efficiency of mRNA delivery in the liver using functionalized phospholipids.
Main Methods:
- Chemical engineering of 1,2-dioleoyl-3-sn-glycero-phosphoethanolamine (DOPE) to create DOPE-Cx, a zwitterionic phospholipid.
- Designing DOPE-Cx with hydrophobic moieties to induce specific lipid-phase transitions (cubic phase) upon interaction with phosphatidylcholine (PC).
- Evaluating mRNA delivery efficiency in the liver using the engineered DOPE-Cx phospholipids.
Main Results:
- DOPE-Cx, when mixed with PC, induces a cubic phase instead of a hexagonal phase, unlike naturally occurring phospholipids.
- This cubic phase induction facilitates membrane fusion, thereby enhancing endosomal escape.
- The engineered DOPE-Cx phospholipids significantly improved functional mRNA delivery in the liver compared to standard phospholipids.
Conclusions:
- Engineered zwitterionic phospholipids like DOPE-Cx can overcome the limitations of natural phospholipids in LNPs.
- DOPE-Cx promotes efficient endosomal escape through induction of non-lamellar lipid phases.
- Functionalized phospholipids represent a promising strategy for advancing therapeutic applications of mRNA.
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