Choline phosphate synergistic STING activation nitrogenous heterocycles engineered dendrimers enhance mRNA tumor vaccine delivery

Dendrimer-functionalized LNPs provide a strategy to enhance tumor vaccine efficacy. • Choline phosphate-modified PAMAM improves biosafety and mRNA transfection efficiency. • PC7A-modified dendrimers activate STING signaling and promote DC maturation. Polyamine-based lipid nanoparticles (LNPs) are considered a highly promising strategy for tumor therapy due to their exceptional endosomal release and cytoplasmic transfection efficiency. However, the high density of amino groups in polyamine-based lipid nanoparticles leads to low biosafety and immunogenicity, resulting in suboptimal tumor efficacy. Here, we report functional components synthesized by modifying polyamide amine (PAMAM) dendrimers with choline phosphate (CP) group, linoleic acid chains (L18), and a nitrogenous heterocycles (PC7A) molecule to enhance the mRNA delivery efficiency and immunogenicity against tumors associated with standard LNPs. Incorporating functional components into LNPs enables the effective disruption of endosomal structures—while ensuring biosafety—thereby facilitating the efficient and stable delivery of antigenic mRNA. Simultaneously, PC7A, acting as an activator of interferon gene stimulating factors, promotes dendritic cells (DCs) maturation, further enhancing the immunogenicity of LNPs. After the injection of the nanovaccines into mice, the massive generation and recruitment of tumor-specific cytotoxic T cells further enhanced the efficacy of immunotherapy, providing a new strategy for the synergistic enhancement of LNP-based functional components in tumor vaccines. Modifying dendrimers with choline phosphate (CP) groups, linoleic acid (L18), and nitrogen-containing seven-membered heterocyclic molecule (PC7A) can effectively improve the performance of mRNA-LNPs. These enhancements include reduced biotoxicity, increased endosome escape, and STING pathway activation-mediated immunogenicity, which can effectively improve the efficacy of vaccines in cancer treatment. Download: Download high-res image (133KB) Download: Download full-size image