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Updated: Feb 15, 2026
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Aromatic Ionizable Lipids Enhance mRNA Delivery via Coordinating Multiple Mechanisms
Lixin Lin1, Xinyue Zhang1, Xinxin Yan1
1College of Pharmaceutical Sciences, Liangzhu Laboratory, Zhejiang University, Hangzhou 310058, China.
Journal of the American Chemical Society
|February 14, 2026
Summary
Researchers developed novel aromatic ionizable lipids to improve messenger RNA (mRNA) delivery using lipid nanoparticles (LNPs). This new LNP platform significantly enhances mRNA delivery efficiency in vivo, outperforming current standards.
Area of Science:
- Biotechnology
- Materials Science
- Drug Delivery
Background:
- Lipid nanoparticles (LNPs) are crucial for mRNA delivery and therapeutics.
- Current LNP delivery efficacy is suboptimal, necessitating advancements in lipid chemistry and mechanistic understanding.
Purpose of the Study:
- To design and evaluate a library of aromatic ionizable lipids for enhanced mRNA delivery.
- To elucidate the mechanisms by which aromatic incorporation improves LNP performance.
Main Methods:
- Synthesized and screened over 900 aromatic ionizable lipids.
- Investigated LNP-mRNA binding affinity, encapsulation efficiency, membrane fluidity, cellular uptake, and endosomal escape.
- Assessed in vivo mRNA delivery efficacy following intravenous and intramuscular administration.
Main Results:
- Aromatic incorporation significantly enhanced LNP-mRNA binding and encapsulation efficiency.
- Aromatic modifications improved membrane fluidity, leading to superior cellular uptake and endosomal escape.
- The optimized aromatic LNPs demonstrated substantially enhanced in vivo mRNA delivery, with the top candidate showing nearly a tenfold increase compared to SM-102 LNPs.
Conclusions:
- Aromatic ionizable lipids represent a promising platform for robust and efficient mRNA delivery.
- Structural exploitation of aromatic functionalities provides valuable insights into the rational design of ionizable lipids.
- This study advances LNP technology for mRNA therapeutics by addressing key delivery bottlenecks.
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