Serum Exposure: A Double-Edged Sword for mRNA-LNPs
When lipid nanoparticles (LNPs) meet blood serum, they don’t stay the same. A recent study, "Effects of Serum Incubation on Lipid Nanoparticle PEG Shedding, mRNA Retention, and Membrane Interactions," by Simon Niederkofler and Fredrik Höök, and their team at Chalmers University of Technology, Sweden, reveals how serum proteins reshape LNPs, boosting their ability to fuse with endosomal membranes while simultaneously compromising mRNA retention.

Key Findings:
PEG Shedding: Serum incubation triggered PEG-lipid desorption, ~ 36 % of the PEG-lipids detached from the LNPs, with a half-life of roughly 10 mins, reducing steric hindrance and enhancing fusion efficiency.

mRNA Release: Up to ~ 35 % of mRNA cargo was lost after serum exposure in some formulations, with smaller LNPs showing more pronounced release.

Fusion Efficiency: Serum-preincubated LNPs fused more effectively with endosomal membrane mimics at moderately acidic pH (6.5-6.0), compared to pristine LNPs.

Why It Matters:
These findings highlight a critical trade-off: serum-induced modifications improve endosomal escape but reduce mRNA retention. Stability assessments in buffer alone are insufficient; systematic testing in serum should be considered a standard quality control step, as it represents a more physiologically relevant environment. Moreover, the optimization of PEG chemistry (type and molar ratio) is pivotal, as it directly influences protein corona formation and thereby dictates LNP behavior in circulation and at the endosomal interface. Together, these insights pave the way for rational design of next-generation LNPs that balance stability, retention, and delivery efficiency.

Read more: https://pubs.acs.org/doi/10.1021/acsami.5c17052