Scientific reportsOct 31, 2025

How mechanical stress may change the structure of mRNA lipid nanoparticles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Prolonged shaking altered surface structure, enlarged particles, and released some unencapsulated RNA.

Evidence

This formulation stress experiment used , , and cryo-EM to compare mRNA-LNPs after 30 and 240 minutes of shaking.

Caveat

The work tested a controlled mechanical-stress condition, not storage, transport, immunogenicity, or clinical performance.

Simplified

The COVID-19 pandemic has demonstrated the suitability of mRNA-lipid nanoparticle (LNP) drug product as an appropriate vaccine for emergency response during a global health crisis. Understanding of mRNA-LNPs stability and mechanisms of degradation is important; however a deeper mechanistic understanding of the impact of liquid-air interfaces on is still absent. This study used a combination of nanoparticle tracking analysis (), nuclear magnetic resonance () spectroscopy and cryogenic electron microscopy (cryo-EM) to elucidate the dynamics occurring during shaking induced stress on mRNA-LNPs. Minimal impact is observed for mRNA-LNPs upon 30 min of shaking. However, a significant increase of particle sizes and heterogeneity, accompanied by a decrease of particle concentrations were observed by NTA upon 240 min of shaking. Cryo-EM imaging showed the formation of larger mRNA-LNP structures, which was consistent with the NTA results. Additionally, unencapsulated RNA was observed with RNA staining after prolonged shaking of mRNA-LNPs. NMR suggests that the mRNA-LNP surface structure changes significantly which was marked by changes in the lipid mobility of the PEGylated and ionizable lipids. NMR also detected distinct sucrose signals owing to the movement from the bulk solution into the larger mRNA-LNPs. Collectively, the suite of these techniques provides a deeper understanding of the dynamics leading to morphological changes of mRNA-LNPs under mechanical stress conditions by shaking.

Key numbers

84.6 nm

Increase in Particle Size

Mean diameter after 240 min of shaking

6.81×10¹² particles/mL

Decrease in Particle Concentration

Particle concentration after 240 min of shaking

52.0 nm

Initial Particle Size

Mean diameter after 30 min of shaking

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How mechanical stress may change the structure of mRNA lipid nanoparticles

Abstract

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