Efficacy of LNP@2DG-DON liposomal nanoparticles in tumor inhibition and immune activation

BACKGROUND: Pancreatic cancer has poor prognosis, and immunotherapy efficacy is limited by PD-L1 stability via GFAT1-mediated glycosylation. We developed LNP@2DG-DON, a liposomal nanoparticle co-delivering glycolysis inhibitor 2DG and GFAT1 inhibitor DON, to enhance antitumor immunity and metabolic targeting. METHODS: LNP@2DG-DON nanoparticles were synthesized using the thin-film dispersion method and characterized for size, stability, drug loading, and release profiles. In vitro studies assessed cytotoxicity, apoptosis, migration, and invasion in ASPC-1 and PANC-1 pancreatic cancer cell lines. In vivo efficacy was evaluated in a subcutaneous xenograft mouse model, measuring tumor growth, immune cell infiltration, and survival. Western blotting, flow cytometry, and immunohistochemistry were employed to analyze molecular and cellular mechanisms. RESULTS: LNP@2DG-DON showed uniform size (100-120 nm), high drug loading (6.84-9.27%), and sustained release. It significantly reduced cell viability, induced apoptosis, and inhibited metastasis in vitro. In vivo, it suppressed tumor growth, prolonged survival, and increased CD8+/NK cell infiltration while reducing immunosuppressive cells. Mechanistically, it downregulated PD-L1/GFAT1 and activated pro-apoptotic pathways. CONCLUSIONS: The dual-targeting LNP@2DG-DON nanoparticle synergistically combines metabolic and immune modulation, demonstrating superior antitumor effects compared to single-agent therapies. This approach represents a promising strategy for pancreatic cancer treatment, warranting further clinical investigation.