In vitro and in vivo evaluation of clinically-approved ionizable cationic lipids shows divergent results between mRNA transfection and vaccine efficacy

Jul 5, 2023Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Lab and animal tests of approved ionizable lipids show different results for mRNA delivery and vaccine effectiveness

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Abstract

Lipid nanoparticles containing ALC-0315 and SM-102 resulted in significantly higher protein expression levels in zebrafish embryos compared to Dlin-MC3-DMA-based nanoparticles.

Ionizable cationic lipids (ICLs) are critical for the effectiveness of lipid nanoparticles (LNPs) used in mRNA delivery.
Four ICLs were examined for their impact on mRNA-LNP performance, showing similar physical properties and mRNA encapsulation efficiencies.
In vitro, SM-102-based LNPs demonstrated superior ability to induce protein expression and activate antigen-specific T cell proliferation.
In vivo, ALC-0315 and SM-102 LNPs produced comparable protein expression levels, which were significantly higher than those from Dlin-MC3-DMA.
A mouse study indicated that while all three clinically-approved ICLs led to high cytokine production from T cells, no significant differences were observed among them.
These findings suggest that ICLs influence mRNA-LNP performance and that in vitro results may not accurately predict in vivo behavior.

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Ionizable cationic lipids (ICLs) play an essential role in the effectiveness of lipid nanoparticles (LNPs) for delivery of mRNA therapeutics and vaccines; therefore, critical evaluations of their biological performance would extend the existing knowledge in the field. In the present study, we examined the effects of the three clinically-approved ICLs, Dlin-MC3-DMA, ALC-0315 and SM-102, as well as DODAP, on the in vitro and in vivo performance of LNPs for mRNA delivery and vaccine efficacy. mRNA-LNPs containing these lipids were successfully prepared, which were all found to be very similar in their physicochemical properties and mRNA encapsulation efficiencies. Furthermore, the results of the in vitro studies indicated that these mRNA-LNPs were efficiently taken up by immortalized and primary immune cells with comparable efficiency; however, SM-102-based LNPs were superior in inducing protein expression and antigen-specific T cell proliferation. In contrast, in vivo studies revealed that LNPs containing ALC-0315 and SM-102 yielded almost identical protein expression levels in zebrafish embryos, which were significantly higher than Dlin-MC3-DMA-based LNPs. Additionally, a mouse immunization study demonstrated that a single-dose subcutaneous administration of the mRNA-LNPs resulted in a high production of intracellular cytokines by antigen-specific T cells, but no significant differences among the three clinically-approved ICLs were observed, suggesting a weak correlation between in vitro and in vivo outcomes. This study provides strong evidence that ICLs modulate the performance of mRNA-LNPs and that in vitro data does not adequately predict their behavior in vivo.

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In vitro and in vivo evaluation of clinically-approved ionizable cationic lipids shows divergent results between mRNA transfection and vaccine efficacy

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