Polymersome Nanoreactor-Mediated Combination Chemodynamic-Immunotherapy via ROS Production and Enhanced STING Activation

Stimulator of interferon genes (STING) activation by STING agonists has been recognized as one of important immunotherapy strategies. However, immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy. Herein, ferrocene-containing polymersome nanoreactors are engineered by co-loading glucose oxidase (GOD) and STING agonist, symmetry-linked amidobenzimidazole (DiABZI), for enhanced STING activation and combination chemodynamic-immunotherapy. After intravenous injection, the polymersomes can accumulate in tumor tissues. The tumor acidity-triggered polymersome membrane permeability allows the entrance of tumoral glucose and oxygen for H₂O₂ production by GOD, which is further transformed into hydroxyl radicals (•OH) under the catalysis of ferrocene moieties. Chemodynamic therapy (CDT) based on •OH can induce efficient cellular apoptosis and release of fragmented DNA and tumor-associated antigens to promote endogenous STING activation and reverse immunosuppressive tumor microenvironment. Simultaneously, pH-responsive release of DiABZI activates STING pathway to elicit antitumor immune responses. Therefore, DiABZI and CDT synergistically enhance the antitumor immunity via combination chemodynamic-immunotherapy. The primary tumors are completely ablated and the growth of distant tumors that are established after treatment is also suppressed efficiently. The polymersome nanoreactor-mediated chemodynamic-immunotherapy represents a promising treatment strategy toward primary solid and metastatic tumors.