Dendritic Cell‐Hitchhiking In Vivo for Vaccine Delivery to Lymph Nodes

Abstract Therapeutic cancer vaccines are among the first FDA‐approved cancer immunotherapies. Among them, it remains a major challenge to achieve robust lymph‐node (LN) accumulation. However, delivering cargo into LN is difficult owing to the unique structure of the lymphatics, and clinical responses have been largely disappointing. Herein, inspired by the Migrated‐DCs homing from the periphery to the LNs, an injectable hydrogel‐based polypeptide vaccine system is described for enhancing immunostimulatory efficacy, which could form a local niche of vaccine “hitchhiking” on DCs. The OVA peptide modified by lipophilic DSPE domains in the hydrogel is spontaneously inserted into the cell membrane to achieve “antigen anchoring” on DCs in vivo. Overall, OVA peptide achieves active access LNs through recruiting and “hitchhiking” subcutaneous Migrated‐DCs. Remarkably, it is demonstrated that the composite hydrogel enhances LNs targeting efficacy by approximately six‐fold compared to free OVA peptide. Then, OVA peptide can be removed from the cell surface under a typical acidic microenvironment within the LNs, further share them with LN‐resident APCs via the “One‐to‐Many” strategy (One Migrated‐DC corresponding to Many LN‐resident APCs), thereby activating powerful immune stimulation. Moreover, the hydrogel vaccine exhibits significant tumor growth inhibition in melanoma and inhibits pulmonary metastatic nodule formation.