In Situ Vaccination with An Injectable Nucleic Acid Hydrogel for Synergistic Cancer Immunotherapy

Abstract Recently, therapeutic cancer vaccines have emerged as promising candidates for cancer immunotherapy. Nevertheless, their efficacies are frequently impeded by challenges including inadequate antigen encapsulation, insufficient immune activation, and immunosuppressive tumor microenvironment. Herein, we report a three‐in‐one hydrogel assembled by nucleic acids (NAs) that can serve as a vaccine to in situ trigger strong immune response against cancer. Through site‐specifically grafting the chemodrug, 7‐ethyl‐10‐hydroxycamptothecin (also known as SN38), onto three component phosphorothioate (PS) DNA strands, a Y‐shaped motif (Y‐motif) with sticky ends is self‐assembled, at one terminus of which an unmethylated cytosine‐phosphate‐guanine (CpG) segment is introduced as an immune agonist. Thereafter, programmed cell death ligand‐1 (PD‐L1) siRNA that performs as immune checkpoint inhibitor is designed as a crosslinker to assemble with the CpG‐ and SN38‐containing Y‐motif, resulting in the formation of final NA hydrogel vaccine. With three functional agents inside, the hydrogel can remarkably induce the immunogenic cell death to enhance the antigen presentation, promoting the dendritic cell maturation and effector T lymphocyte infiltration, as well as relieving the immunosuppressive tumor environment. When inoculated twice at tumor sites, the vaccine demonstrates a substantial antitumor effect in melanoma mouse model, proving its potential as a general platform for synergistic cancer immunotherapy.