A Nanobody-LNP Platform for Targeting and Relicensing Dendritic Cells for Potent Cancer Immunotherapy
Shugang Qin1,2, Zhiying Huang1, Hai Huang1
1Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Effective cancer immunotherapy requires not only efficient antigen delivery to dendritic cells (DCs) but also overcoming local immunosuppression. Here, we introduce a nanobody-LNP platform that achieves both targeting and active relicensing of DCs. By decorating lipid nanoparticles with nanobodies against the DC surface protein Plastin-2 (PLS2), our platform achieves a remarkable 93% internalization efficiency. This preferential targeting dramatically enhances antigen expression while simultaneously relicensing DCs toward a more potent, mature phenotype by inhibiting the immunosuppressive Leptin-JAK2-STAT3 signaling pathway. This integrated strategy unleashed potent cytotoxic T lymphocyte responses and led to marked inhibition of established tumors. Our work establishes PLS2 as a novel immunomodulatory receptor and presents a dual-action delivery platform that significantly boosts cancer vaccine potency.
