Smaller-sized (LNPs) with neutral charge showed superior transfection efficiency after intramuscular injection.
Lipid nanoparticles are a widely used non-viral gene delivery system.
The size and charge of LNPs significantly affect their transfection efficiency but not their in vivo distribution.
Shorter acyl chains in enhance transfection efficiency by improving cellular uptake and escape from lysosomes.
Different types of PEGylated lipids lead to varying cellular uptake mechanisms among the LNPs.
Simplified
(LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs.
Key numbers
1.5×
Transfection Efficiency Increase
Compared to with lower PEGylated lipid content.
94.61 nm
Particle Size
Average diameter of smaller-sized .
12.83 mV
Charge Comparison
Charge of with 15% DOTAP.
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