Nature biotechnologyOct 23, 2025

Understanding the makeup and features of fat-based nanoparticles using physical analysis

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Lipid nanoparticles (LNPs) display intrinsic polydispersity in size, RNA loading, and shape, influenced by formulation techniques and lipid composition.

Traditional methods struggle to accurately quantify the physicochemical properties of LNPs.
Emerging solution-based biophysical techniques provide higher resolution data beyond size and polydispersity.
The intrinsic properties of LNPs may affect their performance in delivering mRNA.
A relationship exists between mRNA translation and the physicochemical characteristics of LNPs.
Solution-based methods are likely to inform the design of LNPs for improved clinical applications.

Simplified

Designing lipid nanoparticle (LNP) delivery systems with specific targeting, potency and minimal side effects is crucial for their clinical use. However, traditional characterization methods, such as dynamic light scattering, cannot accurately quantify physicochemical properties of LNPs and how these are influenced by the lipid composition and mixing method. Here, we structurally characterize polydisperse LNP formulations by applying emerging solution-based biophysical methods that have higher resolution and provide biophysical data beyond size and polydispersity. These techniques include sedimentation velocity analytical ultracentrifugation, field-flow fractionation followed by multiangle light scattering and size-exclusion chromatography in line with synchrotron small-angle X-ray scattering. We show that LNPs have intrinsic polydispersity in size, RNA loading and shape, which depend on both the formulation technique and the lipid composition. Lastly, we predict LNP transfection in vitro and in vivo by examining the relationship between mRNA translation and physicochemical characteristics. Solution-based biophysical methods will be essential for determining LNP structure-function relationships, facilitating the creation of new design rules for LNPs.

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Competing interests

Competing interests: The authors declare no competing interests.

PubMed

Understanding the makeup and features of fat-based nanoparticles using physical analysis

Abstract

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Competing interests

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Abstract

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