A Nanobody‐LNP Platform for Targeting and Relicensing Dendritic Cells for Potent Cancer Immunotherapy

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.