Radioactive hydrogel with NETs degradation capacity for the boosted tumor radio-immunotherapy

Radioisotope therapy is a clinically effective cancer treatment. However, its therapeutic efficacy is limited by the short retention time of radioisotopes and multiple tumor radiation resistance mechanisms in tumor. Neutrophil extracellular traps (NETs), whose formation is enhanced under ionizing radiation exposure, can reduce tumor radiation response and interfere with the anti-tumor effects of immune cells. Herein, we labeled carboxymethyl chitosan methacryloyl (CMCSMA) with iodine-131 (¹³¹I) and then mixed it with deoxyribonuclease I (DNase I) to prepare a photocurable hydrogel (¹³¹I-CMCSMA/DNase I gel) for the treatment of colorectal tumor. Upon intratumoral injection, the ¹³¹I-CMCSMA/DNase I hydrogel rapidly solidified in situ after UV irradiation, resulting in prolonged retention of ¹³¹I and sustained release of DNase I within the tumor. The retained ¹³¹I significantly inhibited the growth of the local tumor while increasing NETs formation. Meanwhile, DNase I degraded the NETs, thus amplifying the ¹³¹I-induced immunogenic cell death and anti-tumor immune response. In this way, the ¹³¹I-CMCSMA/DNase I gel effectively inhibited both primary and distant tumor growth. Therefore, this approach realizes efficient radio-immunotherapy of tumors by attaching the therapeutic radioisotope to hydrogel scaffolds and combining radiotherapy with a NETs-degrading enzyme, providing a novel strategy to enhance radioisotopes-stimulated immunotherapy.