Spleen-selective co-delivery of mRNA and TLR4 agonist-loaded LNPs for synergistic immunostimulation and Th1 immune responses

🥉 Top 5% JournalMar 27, 2023Journal of controlled release : official journal of the Controlled Release Society

Targeted delivery of mRNA and immune-activating molecules to the spleen to boost immune responses

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Spleen-selective mRNA vaccines induced a potent antigen-specific cytotoxic T cell immune response and prevented tumor growth in a mouse model.

Spleen-targeted delivery of unmodified mRNA and TLR agonists resulted in a persistent antitumor cellular immune response.
Lipid nanoparticles co-loaded with ovalbumin-coding mRNA and TLR4 agonists effectively facilitated tissue-specific mRNA expression in the spleen.
The combination of mRNA antigens and TLR agonists enhanced Th1 immune responses by activating multiple Toll-like receptors.
In a prophylactic mouse model, the vaccine prevented the growth of EG.7-OVA tumors and provided immune memory protection.
The treatment also delayed tumor growth in subcutaneously transplanted lymphoma and reduced lung metastasis of melanoma.

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Spleen is an ideal site for initiating and amplifying antigen-specific immune response. However, spleen-selective antigen delivery has limited tumor therapeutic efficacy owing to an inadequate cytotoxic T-cell immune response. In this study, we designed a spleen-selective mRNA vaccine that delivered unmodified mRNA and Toll-like Receptor (TLR) agonists to the spleen after systemic administration, resulting in a sufficient and persistent antitumor cellular immune response with potent tumor immunotherapeutic efficacy. To establish potent tumor vaccines (sLNPs-OVA/MPLA), we co-loaded stearic acid doped lipid nanoparticles with ovalbumin (OVA)-coding mRNA and TLR4 agonists (MPLA). We found that sLNPs-OVA/MPLA facilitated tissue-specific mRNA expression in the spleen after intravenous injection and elicited enhanced adjuvant activity with Th1 immune responses by activating multiple TLRs. In a prophylactic mouse model, sLNPs-OVA/MPLA induced a potent antigen-specific cytotoxic T cell immune response and ultimately prevented the growth of EG.7-OVA tumors with persistent immune memory protection. In addition, sLNPs-OVA/MPLA effectively delayed the tumor growth of EG.7-OVA subcutaneously transplanted lymphoma and lung metastasis formation of B16F10-OVA intravenously injected melanoma. This study showed that the co-delivery of mRNA antigens and appropriate TLR agonists could significantly improve the antitumor immunotherapeutic efficacy of spleen-targeted mRNA vaccines via synergistic immunostimulation and Th1 immune responses.

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Abstract

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