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

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 -, CD4⁺ T -, and CD8⁺ T cells. Furthermore, this formulation elicited robust antigen-specific immune responses, including an elevation in antigen-specific CD8⁺ T 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.