Zn-LNP coordinated nanoassembly-based mRNA vaccines for synergistic spleen-targeted delivery and potent tumor suppression via immunoprophylaxis and immunotherapy

The clinical translation of mRNA vaccines for cancer immunotherapy critically hinges on the development of mRNA nanocarriers that ensure precise organ targeting, potent immune activation, and high biosafety. Here, we reported the novel supramolecularly engineered mRNA nanocarriers based on Zn 2+ -lipid nanoparticle (LNP) coordinated nanoassemblies (NAs), incorporating imidazole-functionalized ionizable lipids and Zn 2+ ions as structural and immunostimulatory components. Specifically, a library of 32 imidazole-based ionizable lipids was synthesized and screened, identifying BR5–2 LNPs as a lead candidate for efficient mRNA transfection. By leveraging the coordination interaction between Zn 2+ and the components of BR5–2 LNPs, we successfully constructed Zn-BR5–2 NAs, which exhibited enhanced in vitro mRNA transfection efficiency and promoted dendritic cell maturation via upregulation of major histocompatibility complex class I (MHC-I) antigen presentation. In vivo , Zn-BR5–2 NA-based vaccines achieved 82% spleen-specific mRNA expression and induced a strong antigen-specific CD8 + T cell response (23.09%). Notably, in a B16-OVA mouse melanoma model, Zn-BR5–2 encapsulating ovalbumin mRNA (Zn-BR5–2/mOVA) elicited potent prophylactic and therapeutic antitumor effects. This work underscores the potential of metal-LNP coordination chemistry in advancing next-generation mRNA vaccines with organ-specific delivery and heightened immunotherapeutic efficacy.