Pulmonary metastasis remains a lethal challenge, necessitating potent mRNA vaccines to establish proactive immune surveillance. Although lipid nanoparticles (LNPs) are the gold standard for delivery mRNA, the "PEG dilemma"-comprising immunogenicity and poor cellular engagement-critically limits their efficacy. Here, we developed a biocompatibility, PEG-free mRNA platform (SG-LNP) co-modified with sialic acid-dimyristoyl-glycerol (SA-DMG) and monosialotetrahexosylganglioside (GM1), enabling a customizable tissue-targeting delivery pathway. This platform leverages the SA-Siglec axis to target antigen-presenting cells (APCs), markedly enhancing APCs uptake and facilitating endosomal escape. Upon pulmonary inhalation, the vaccine directly targets pulmonary APCs, shortening immunological pathways and enabling in situ priming of multiple immune effector cells (dendritic cells, macrophages, natural killer cells, and T cells). Following intravenous administration, it selectively targets splenic APCs to orchestrate a systemic immune surveillance network. Furthermore, leveraging this vaccine platform with tunable delivery routes, we investigated the contributions of local and systemic immune toward the prevention of tumor lung metastasis. We found that inhaled SG-LNP elicit robust local immune activation, leading to markedly reduced melanoma infiltration in the lungs relative to conventional PEG-modified LNPs. Notably, systemic administration of SG-LNP drives more extensive expansion of circulating antigen-specific T cells and natural killer cells (NKs). This systemic mobilization effectively intercepts circulating tumor cells before pulmonary colonization, achieving complete prevention of pulmonary metastasis with 100% protective efficacy. Our findings demonstrate that systemic coordination outperforms localized activation in prophylactic of organ-specific metastasis, providing a strategic blueprint for the design and administration of next-generation PEG-free mRNA vaccines.
