Lipid nanoparticles with prazole adjuvant to enhance the efficacy of mRNA cancer vaccines

🥉 Top 5% JournalApr 23, 2025Journal of controlled release : official journal of the Controlled Release Society

Lipid nanoparticles with prazole booster to improve mRNA cancer vaccines

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

The formulation combining lipid nanoparticles with esomeprazole increased mRNA antigen expression and enhanced immune responses.

The combination of lipid nanoparticles and esomeprazole improved cytoplasmic release of mRNA by increasing endo-/lysosomal pH.
This formulation altered fibroblast activity through the TGF-β signaling pathway, modifying extracellular matrix composition.
Enhanced penetration of lipid nanoparticles and mRNA into cellular spheroids was observed with the esomeprazole-containing formulation.
Robust immune responses were stimulated, activating dendritic cells as well as CD4T and CD8T cells.
The formulation led to an increase in antigen-specific CD8T cells and significant elevation of antigen-specific IgG levels.
Prolonged and strengthened protection against melanoma was associated with the improved immune response from the combined formulation.

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Although Food and Drug Administration (FDA)-approved lipid nanoparticles (LNPs) exhibit reliable efficiency in mRNA delivery, they still encounter certain challenges owing to biological barriers. Specifically, LNPs have poor cytoplasmic release owing to endo-/lysosomal barriers. Additionally, extracellular barriers such as the extracellular matrix (ECM) hinder particle movement and reduce cellular uptake efficiency. In this study, we developed newly designed formulations using a combination of LNPs and esomeprazole (ESO) as an adjuvant to improve mRNA cytoplasmic release and enhance particle dynamics within the ECM in vivo. The ESO-containing LNP formulation increased endo-/lysosomal pH, resulting in reduced membrane integrity and facilitating the escape of mRNA from the endo-/lysosomes. Additionally, this formulation modulated fibroblast activity through the TGF-β signaling pathway, which altered the ECM composition and enhanced LNP and mRNA penetration into cellular spheroids. Our results demonstrated that the LNP formulation combined with ESO improved mRNA antigen expression both in vitro and in vivo. Notably, the increased mRNA antigen expression induced by the ESO-containing formulation successfully stimulated immune responses, resulting in the activation of dendritic -, CD4T -, and CD8T cells. Furthermore, this formulation elicited robust antigen-specific immune responses, including an elevation in antigen-specific CD8T cells and a significant increase in antigen-specific IgG levels. The enhanced immune response resulting from the combined formulation during vaccination enabled prolonged and strengthened protection against melanoma. Thus, these newly designed formulations combining ESO and LNPs offer significant value and represent a promising strategy for mRNA-based therapeutic applications. + + +

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