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Background <p>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.</p> Methods <p>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.</p> Results <p>LNP@2DG-DON showed uniform size (100–120&#xa0;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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月5日

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  • Jianang Li,
  • Jiale Feng,
  • Runjie Liu,
  • Yueshan Du,
  • Yueheng Li,
  • Liang Liu,
  • Lei Zhang

摘要

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.