Lipid nanoparticles (LNPs), a nonviral nucleic acid delivery
system,
have shown vast potential for vaccine development and disease treatment.
LNPs assist mRNA to cross physiological barriers such as cell membranes
and endosomes/lysosomes, promoting the intracellular presentation
of mRNA. However, the endosome escape efficiency and biosafety of
currently commercialized LNPs are still unsatisfactory, resulting
in underutilization of mRNA. Herein, we report that fluorinated modification
of the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene
glycol)-2000 (PEG-DSPE), termed as FPD, in the LNPs can improve the
delivery efficiency of mRNA. FPD accounts for only 1.5% of lipids
in LNPs but could mediate a 5-fold and nearly 2-fold enhancement of
mRNA expression efficiency in B16F10 tumor cells and primary dendritic
cells, respectively. Mechanism studies reveal that FPD promotes the
cellular internalization of LNPs as well as endosome escape. In vivo studies substantiate that FPD can augment overall
mRNA expression at least 3-fold, either by intravenous or intraperitoneal
injection, compared to LNPs prepared with nonfluorinated PEG-lipids
at a relatively low mRNA dose. Besides, with the introduction of FPD,
mRNA expression in the spleen augmented compared to that of the DMG-PEG
commercial formulations. Benefiting from a prudent dosage of fluorine,
the fluorinated LNPs display favorable biosafety profiles at cellular
and zoological levels.