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Reducing Complexity in Lipid Nanoparticles: Three-Component Zwitterionic Amino Lipids for Targeted Extrahepatic mRNA

Joshua J Robinson¹, Di Zhang¹, Pratima Basak¹

¹Department of Biomedical Engineering, Program in Genetic Drug Engineering, Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

ACS Biomaterials Science & Engineering

|July 9, 2025

Summary

Researchers developed simpler, 3-component zwitterionic amino lipid (ZAL) nanoparticles for mRNA delivery. Chemical modifications improved biocompatibility, efficacy, and enabled organ-specific delivery beyond the liver.

Keywords:

drug delivery lipid nanoparticles lipid synthesis mRNA

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Area of Science:

Biotechnology
Materials Science
Pharmaceutical Sciences

Background:

Lipid nanoparticles (LNPs) are crucial for mRNA vaccine and medicine delivery.
Current LNP formulations often use four lipid components, limiting simplicity and chemical exploration.
Zwitterionic amino lipid (ZAL) LNPs offer a simpler, three-component alternative with potential for targeted delivery.

Purpose of the Study:

To synthesize and evaluate novel Zwitterionic Amino Lipid (ZAL) nanoparticles with chemical modifications.
To assess the impact of these modifications on biocompatibility, mRNA delivery efficacy, and organ-specific targeting.
To establish a framework for chemically engineering LNPs for enhanced therapeutic applications.

Main Methods:

Synthesis of ZALs modified at the secondary hydroxyl position with opivalate, chloride, bromide, and acetate.
In vitro and in vivo evaluation of LNP formulations for mRNA delivery efficiency and organ distribution.
Analysis of structure-activity relationships between chemical modifications and delivery performance.

Main Results:

Novel ZAL derivatives demonstrated improved biocompatibility and enhanced mRNA delivery efficacy.
Specific chemical modifications led to distinct extrahepatic organ-specific delivery profiles.
The acetate-modified ZAL showed superior immune cell transfection in an organ-specific manner.

Conclusions:

A simplified three-component ZAL LNP system can be chemically engineered for effective mRNA delivery.
Modifications at the secondary hydroxyl position provide a strategy for achieving organ-specific targeting.
This research expands the chemical scope of LNPs for extrahepatic delivery, offering a roadmap for simpler, more effective mRNA therapeutics.