Self-Illuminating In Situ Hydrogel with Immune-Adjuvant Amplify Cerenkov Radiation-Induced Photodynamic Therapy.

Cerenkov radiation-induced photodynamic therapy (CR-induced PDT) has shown the potential to overcome the light penetration limitation in conventional PDT. In addition, the tumor-associated antigens (TAAs) produced by PDT can initiate an antitumor immune process but only show a limited immunotherapeutic effect without the use of immunotherapeutic agents. Herein, a CR-induced PDT hydrogel (R837/Zr-HG-PpIX) has been developed by in situ formation of a hyaluronic acid (HA)-based hydrogel integrated with internal light source Zr, photosensitizer protoporphyrin IX (PpIX), and immune adjuvant imiquimod (R837). The obtained R837/Zr-HG-PpIX hydrogel with long-term tumor retention and low radiation leakage can provide long-lasting photodynamic therapy without phototoxicity in normal tissues. In addition, the loaded R837 improves the immunogenicity of TAAs released after PDT, resulting in considerably enhanced immune responses. At relatively low radioactivity, R837/Zr-HG-PpIX shows significant inhibition in subcutaneous H22 tumor-bearing BALB/c mice and orthotopic VX2 liver tumor-bearing rabbits. Furthermore, the combination of such a CR-induced PDT hydrogel with anti-PD-L1 exhibits the abscopal effect to inhibit the growth of distant tumors. Therefore, the proposed in situ formed CR-induced PDT hydrogel with long-term photodynamic-immunotherapy provides an effective strategy for deep tumor therapy.