MnO₂@CeO_x-GAMP radiosensitizer with oxygen vacancies depended mimicking enzyme-like activities for radiosensitization-mediated STING pathway activation.

Abstract

Activation of the stimulator of interferon genes (STING) pathway by radiotherapy (RT) has a significant effect on eliciting antitumor immune responses. The generation of hydroxyl radical (·OH) storm and the sensitization of STING-relative catalytic reactions could improve radiosensitization-mediated STING activation. Herein, multi-functional radiosensitizer with oxygen vacancies depended mimicking enzyme-like activities was fabricated to produce more dsDNA which benefits intracellular 2', 3'-cyclic GMP-AMP (cGAMP) generation, together with introducing exogenous cGAMP to activate immune response. MnO₂@CeO_x nanozymes present enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities due to induced oxygen vacancies accelerate the redox cycles from Ce⁴⁺ to Ce³⁺ via intermetallic charge transfer. CeO_x shells not only serve as radiosensitizer, but also provide the conjugation site for AMP/GMP to form MnO₂@CeO_x-GAMP (MCG). Upon X-ray irradiation, MCG with SOD-like activity facilitates the conversion of superoxide anions generated by Ce-sensitization into H₂O₂ within tumor microenvironment (TME). The downstream POD-like activity catalyzes the elevated H₂O₂ into a profusion of ·OH for producing more damage DNA fragments. TME-responsive decomposed MCG could supply exogenous cGAMP, meanwhile the releasing Mn²⁺ improve the sensitivity of cyclic GMP-AMP synthase to dsDNA for producing more cGAMP, resulting in the promotion of STING pathway activation.