Cancer Radiosensitization Nanoagent to Activate cGAS-STING Pathway for Molecular Imaging Guided Synergistic Radio/Chemo/Immunotherapy.

Immunotherapy has emerged as an innovative strategy with the potential to improve outcomes in cancer patients. Recent evidence indicates that radiation-induced DNA damage can activate the cGAS-STING pathway to enhance the antitumor immune response. Even so, only a small fraction of patients currently benefits from radioimmunotherapy due to the radioresistance and the inadequate activation of the cGAS-STING pathway. Herein, we integrated HfO 2 nanoparticles (radiosensitizer) and SN38 (chemotherapy drug, STING agonist) into a polydopamine-coated core-shell nanoplatform (HfO 2 @PDA/Fe/SN38) to achieve synergistic chemoradiotherapy and immunotherapy. The co-delivery of HfO 2 /SN38 greatly enhanced radiotherapy efficacy by effectively activating the cGAS-STING pathway, which then triggered dendritic cells maturation and CD8 + T cells recruitment. Consequently, the growth of both primary and abscopal tumors in tumor-bearing mice was efficiently inhibited. Moreover, the HfO 2 @PDA/Fe/SN38 complexes exhibited favorable MR/photoacoustic bimodal molecular imaging properties. In summary, our developed multifunctional complexes have the potential to intensify immune activation to realize simultaneous cancer Radio/Chemo/Immunotherapy for clinical translation. This article is protected by copyright. All rights reserved.