Ionizable guanidine-based lipid nanoparticle for targeted mRNA delivery and cancer immunotherapy

🥈 Top 2% JournalOct 24, 2025Science advances

Special lipid nanoparticles with guanidine groups for targeted mRNA delivery and cancer immune treatment

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Abstract

Guanidine-LNPs enable efficient mRNA delivery to the spleen and enhance antigen presentation.

Guanidine-LNPs can deliver mRNA to the spleen after intravenous administration.
They preferentially target antigen-presenting cells compared to conventional amine-LNPs.
Guanidine-LNPs lead to significantly enhanced antigen presentation and T cell activation.
mRNA vaccines using guanidine-LNPs elicit strong and specific immune responses.
Complete protection against tumor progression was observed with the guanidine-LNPs.
Intraperitoneal administration of guanidine-LNPs allowed selective mRNA expression in the pancreas.

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The development of lipid nanoparticle (LNP) systems has largely advanced RNA therapeutics, particularly mRNA-based cancer immunotherapy. Conventional amine-LNPs, designed for hepatic RNA delivery, face challenges in targeting lymphoid organs effectively and maximize antigen presentation. In this study, we present the development of pH-responsive ionizable guanidine-LNPs (G-LNPs). Our cholesterol-free G-LNP system enables efficient delivery of mRNA to the spleen following intravenous administration. Notably, while both amine-LNPs and G-LNPs can deliver mRNA to the spleen, G-LNPs exhibit a unique ability to preferentially target antigen-presenting cells, leading to significantly enhanced antigen presentation and robust T cell activation. mRNA vaccines formulated with G-LNPs elicited strong and antigen-specific immune responses, providing complete protection against tumor progression. In addition, intraperitoneal administration of G-LNPs enabled selective mRNA expression in the pancreas, showcasing the versatility of this delivery platform. These findings underscore the potential of guanidine-LNPs as a highly promising platform for organ-targeted mRNA delivery and cancer immunotherapy.

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