Screening Natural Cholesterol Analogs to Assemble Self‐Adjuvant Lipid Nanoparticles for Antigens Tagging Guided Therapeutic Tumor Vaccine

The clinical progress of tumor nucleotide vaccines is limited due to insufficient recognition and killing of tumor cells with low antigen expression by cytotoxic T lymphocytes (CTL). Here, natural cholesterol analogs are screened to assemble self‐adjuvant lipid nanoparticles (LNPs) for antigens tagging tumor cells and dendritic cells (DC) activation. First, a library of ginsenosides are collected, and then screened according to their anti‐tumor immunity. Then, ginsenoside‐Rg3 based‐LNPs loaded with antigens (Rg3‐LNPs) are identified as the optimal formulation by investigating the physicochemical and biological properties. Finally, Rg3‐LNPs and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) are co‐loaded into a macroporous hydrogel for long‐term immune response. Rg3‐LNPs could accumulate into both tumors and LNs. Rg3‐LNPs targeted tumor cells with high glucose transporter‐1 expression via the targeting ligand Rg3, and anchored antigens on the tumor cell surface, thus promoting the recognition of CTL to tumor cells; Rg3‐LNPs can accumulate into the LNs to promote DC activation and antigen presentation, thus stimulating CTL activation. Besides, Rg3, as an adjuvant, cooperated with GM‐CSF to remodel the tumor microenvironment, thus promoting the killing of CTL to tumor cells. Collectively, this work highlights the importance of tagging antigens to tumor cells in tumor vaccine and has great clinical value for immune‐escaping tumors.