Zn(II)-adjuvanted imidazole-based lipid nanoparticles for potent spleen-targeted mRNA delivery and enhanced immune activation.

Lipid nanoparticles (LNPs) have emerged as a powerful nanoplatforms contributing to the success of mRNA vaccines. However, the rational design of lipid structures and the optimization of LNP composition, especially via metal-based adjuvants to boost extrahepatic delivery and immune responses, represent a promising yet technically challenging strategy. Herein, we developed a Zn(II)-adjuvanted imidazole-based LNP system that integrates rational lipid design with metal-coordinated self-assembly to achieve synergistic enhancement in delivery and immunogenicity. Initially, a library of 28 imidazole-based ionizable lipids was synthesized and screened, identifying A10-1 LNPs with a well-balanced lipid composition and high transfection efficiency. Furthermore, Zn2+ coordination with the imidazole headgroup imparts Zn-A10-1 LNPs with enhanced structural stability and delivery performance, leading to improved cellular uptake, efficient endosomal escape, and preferential accumulation in the spleen. These attributes contributed to the robust activation of bone marrow-derived dendritic cells (BMDCs), induced memory T cell responses, and elevated proinflammatory cytokine secretion. In a melanoma model, vaccination with Zn-A10-1 LNPs markedly suppressed tumor progression and promoted the infiltration of OVA-specific CD8+ T cells. Overall, this study underscores the potential of Zn(II)-coordinated LNPs as effective nanoplatforms for extrahepatic mRNA vaccine delivery, offering a promising strategy for the mRNA-based vaccine design and immunotherapies.