Programming Injectable DNA Hydrogels Yields Tumor Microenvironment‐Activatable and Immune‐Instructive Depots for Augmented Chemo‐Immunotherapy

Abstract Injectable hydrogels have attracted increasing attention for promoting systemic antitumor immune response through the co‐delivery of chemotherapeutics and immunomodulators. However, the biosafety and bioactivity of conventional hydrogel depots are often impaired by insufficient possibilities for post‐gelling injection and means for biofunction integration. Here, an unprecedented injectable stimuli‐responsive immunomodulatory depot through programming a super‐soft DNA hydrogel adjuvant is reported. This hydrogel system encoded with adenosine triphosphate aptamers can be intratumorally injected in a gel formulation and then undergoes significant molecular conformation change to stimulate the distinct release kinetics of co‐encapsulated therapeutics. In this scenario, doxorubicin is first released to induce immunogenic cell death that intimately works together with the polymerized cytosine‐phosphate‐guanine oligodeoxynucleotide (CpG ODN) in gel scaffold for effectively recruiting and activating dendritic cells. The polymerized CpG ODN not only enhances tumor immunogenicity but minimizes free CpG‐induced splenomegaly. Furthermore, the subsequently released anti‐programmed cell death protein ligand 1 (aPDL1) blocks the corresponding immune inhibitory checkpoint molecule on tumor cells to sensitize antitumor T‐cell immunity. This work thus contributes to the first proof‐of‐concept demonstration of a programmable super‐soft DNA hydrogel system that perfectly matches the synergistic therapeutic modalities based on chemotherapeutic toxicity, in situ vaccination, and immune checkpoint blockade.