Role of PEGylated lipid in lipid nanoparticle formulation for in vitro and in vivo delivery of mRNA vaccines

Jan 28, 2025Journal of controlled release : official journal of the Controlled Release Society

How Modified Lipids Help Lipid Nanoparticles Deliver mRNA Vaccines in Lab and Living Systems

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Abstract

A PEG-lipid molar content exceeding 3.0% significantly reduced the encapsulation efficiency of mRNA in lipid nanoparticles.

Increased PEG-lipid content led to a significant decrease in mRNA translation efficiency.
The lipid tail length of PEG-lipid significantly influenced the properties of mRNA-loaded lipid nanoparticles, regardless of the mixing method used.
LNPs made from ALC-0159 with C14 lipid tails or C16-Ceramide-PEG preferentially accumulated in the liver, while those from C8-Ceramide-PEG were mainly found in lymph nodes.
In a mouse model, mRNA-LNPs from C8-Ceramide-PEG or C16-Ceramide-PEG showed comparable vaccination efficacy to those made from ALC-0159.
Higher anti-PEG antibody responses were induced by C16-Ceramide-PEG and DSPE-PEG LNPs compared to C8-Ceramide-PEG and ALC-0159 LNPs.
All tested LNPs did not cause significant toxicity in mice.

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mRNA-loaded lipid nanoparticles (mRNA-LNPs) hold great potential for disease treatment and prevention. LNPs are normally made from four lipids including ionizable lipid, helper lipid, cholesterol, and PEGylated lipid (PEG-lipid). Although PEG-lipid has the lowest content, it plays a crucial role in the effective delivery of mRNA-LNPs. However, previous studies have yet to elucidate the key factors of PEG-lipid that influence the properties of LNPs. This study reported how PEG-lipid content, lipid tail length, and chemical linkage between PEG and lipid affected in vitro and in vivo properties of mRNA-LNPs. Forty-eight LNP formulations were prepared and characterized. The results revealed that a PEG-lipid molar content exceeding 3.0 % significantly reduced the encapsulation efficiency of mRNA in LNPs via manual mixing. An increased PEG-lipid content also significantly decreased mRNA translation efficiency. Although the chemical linkage had minimal impact, the lipid tail length of PEG-lipid significantly affected the properties of mRNA-LNPs, irrespective of whether the LNPs were prepared using manual or microfluidic mixing. mRNA-LNPs made from ALC-0159 with C14 lipid tails, which is used in Pfizer/BioNTech COVID-19 mRNA vaccines, or C16-Ceramide-PEG preferably accumulated in the liver, while mRNA-LNPs prepared from C8-Ceramide-PEG were largely found in the lymph nodes. In a mouse SARS-CoV-2 Delta variant spike protein-encoded mRNA vaccine model, mRNA-LNPs made from either C8-Ceramide-PEG or C16-Ceramide-PEG yielded comparable vaccination efficacy to mRNA-LNPs made from ALC-0159, while mRNA-LNPs formulated with DSPE-PEG with C18 lipid tails mediated lower vaccination efficacy. C16-Ceramide-PEG LNPs and DSPE-PEG LNPs induced higher anti-PEG antibody response than C8-Ceramide-PEG and ALC-0159 LNPs. All the LNPs tested did not cause significant toxicity in mice. These results offer valuable insights into the use of PEG-lipid in LNP formulations and suggest that C8-Ceramide-PEG holds potential for use in the formulation of mRNA vaccine-loaded LNPs.

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Role of PEGylated lipid in lipid nanoparticle formulation for in vitro and in vivo delivery of mRNA vaccines

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