Modulating Lipid Nanoparticles with Histidinamide‐Conjugated Cholesterol for Improved Intracellular Delivery of mRNA

Feb 12, 2024Advanced healthcare materials

Improving mRNA delivery inside cells by modifying lipid nanoparticles with a special cholesterol compound

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Abstract

The pK values of the Hchol-LNPs are approximately 6.03 and 6.61 in different lipid formulations.

Incorporating an ionizable cholesterol analog, Hchol, into lipid nanoparticles enhances their potency for delivering mRNA.
Hchol-LNPs significantly improve mRNA delivery efficiency by facilitating endosomal escape.
At pH 5.5, Hchol-LNPs show increased effectiveness in causing red blood cell hemolysis, suggesting enhanced membrane destabilization.
Mice treated with Hchol-LNPs exhibit substantially improved mRNA delivery compared to standard formulations.
LNPs containing SARS-CoV-2 spike mRNA vaccinations generate strong antigen-specific antibody responses.

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Recently, mRNA-based therapeutics, including vaccines, have gained significant attention in the field of gene therapy for treating various diseases. Among the various mRNA delivery vehicles, lipid nanoparticles (LNPs) have emerged as promising vehicles for packaging and delivering mRNA with low immunogenicity. However, while mRNA delivery has several advantages, the delivery efficiency and stability of LNPs remain challenging for mRNA therapy. In this study, an ionizable helper cholesterol analog, 3β[L-histidinamide-carbamoyl] cholesterol (Hchol) lipid is developed and incorporated into LNPs instead of cholesterol to enhance the LNP potency. The pKvalues of the Hchol-LNPs are ≈6.03 and 6.61 in MC3- and SM102-based lipid formulations. Notably, the Hchol-LNPs significantly improve the delivery efficiency by enhancing the endosomal escape of mRNA. Additionally, the Hchol-LNPs are more effective in a red blood cell hemolysis at pH 5.5, indicating a synergistic effect of the protonated imidazole groups of Hchol and cholesterol on endosomal membrane destabilization. Furthermore, mRNA delivery is substantially enhanced in mice treated with Hchol-LNPs. Importantly, LNP-encapsulated SARS-CoV-2 spike mRNA vaccinations induce potent antigen-specific antibodies against SARS-CoV-2. Overall, incorporating Hchol into LNP formulations enables efficient endosomal escape and stability, leading to an mRNA delivery vehicle with a higher delivery efficiency. a

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Modulating Lipid Nanoparticles with Histidinamide‐Conjugated Cholesterol for Improved Intracellular Delivery of mRNA

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