X-ray triggered bimetallic nanoassemblies as radiosensitizers and STING agonists for a CDT/radio-immunotherapy strategy.

Radiotherapy (RT) is a cornerstone of cancer therapy, but its effectiveness is constrained by dose-limiting toxicity and inadequate systemic immune activation. To overcome these limitations, we have engineered an X-ray-responsive nanoassembly (sMnAu NAs) by cross-linking monodisperse MnAu nanoparticles (NPs) with radiation-responsive diselenide-containing linkers. MnAu alloy NPs not only provide Au NPs for radiosensitization, but also control Mn (0) release, which stimulates Fenton-like reaction for chemodynamic therapy and is transferred into Mn to activate the STING pathway for immunotherapy. The responsive design not only improves tumor accumulation via EPR effect during circulation, but also achieves deep penetration of MnAu NPs following X-ray induced disassembly. The synergistic combination of chemodynamic therapy, radiotherapy and immunotherapy exhibits remarkable inhibition of tumor growth and metastasis. Overall, our sMnAu NAs represent a promising radiosensitizer for chemodynamic therapy and radiotherapy to enhance immunotherapy. STATEMENT OF SIGNIFICANCE: As a principal treatment modality in cancer management, RT is limited due to the co-irradiation of organs at risk and subsequent normal tissue toxicities. This study reported an X-ray responsive radiosensitizer prepared by cross-linking monodisperse MnAu NPs with diselenide-containing linkers. Upon X-ray irradiation, sMnAu NAs accumulate in tumors and disassemble into MnAu NPs, enabling deeper penetration. The increased surface area of MnAu NPs enhances the exposure of Mn(0), which reacts into Mn and enhances ROS generation. The released Mn activates the STING pathway, potentiating the X-ray-induced immune response. The synergistic integration of CDT, RT, and immunotherapy results in a potent suppression of tumor growth and metastasis. Collectively, this X-ray activatable CDT/radio-immunotherapy strategy holds great potential for effective cancer treatment.