Key Findings
The study demonstrates that LNP shape and internal morphology are functionally relevant design variables that directly influence mRNA loading, cellular uptake, and protein expression. Specifically, non-spherical LNP structures resulted in substantially higher and more sustained protein expression than spherical LNPs. While non-spherical LNPs also showed higher cellular uptake, the researchers noted that this increase was relatively modest and cannot alone explain the significant enhancement in transfection performance.
Technical Details
The researchers found that modulating lipid composition—specifically by increasing DSPC content—drives a structural transition from compact spherical morphologies to vesicular non-spherical morphologies. This transition also altered RNA loading at the single-particle level. These observed trends remained consistent across various LNP formulations utilizing clinically relevant ionizable lipids, including:
- SM-102
- ALC-0315
- DLin-MC3-DMA
Background and Context
Lipid nanoparticles are widely employed for nucleic acid delivery. To date, most optimization efforts in the field have focused on refining formulation features, improving therapeutic efficacy, and enabling extrahepatic targeting. However, particle shape and internal architecture have often been overlooked, despite their critical influence on biodistribution, particle stability, and cellular uptake.
Significance and Outlook
These findings establish that the physical morphology of a nanoparticle is as critical as its chemical composition. By identifying the link between DSPC content, particle shape, and the resulting duration and magnitude of mRNA expression, this research provides a new design variable for the development of next-generation LNPs. Incorporating shape and internal structure into the design process may lead to improved mRNA delivery and enhanced therapeutic outcomes.
Source: https://www.biorxiv.org/content/10.64898/2026.10.18.759824v1
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