Precise and rapid release of X-ray activated autophagy inhibitors for radiotherapy sensitization of hypopharyngeal carcinoma

Protective autophagy represents a major factor responsible for radiotherapy resistance in tumor cells, leading to therapeutic failure, metastasis, and recurrence. Autophagy inhibitors can enhance radiosensitivity by suppressing protective autophagy in tumor. However, the usage of autophagy inhibitors is limited by the issues including non-specific release and delayed delivery. In this work, we develop an X-ray-activatable nanocarrier ZGGC@MON-CQ (ZMC) for precise and rapid release of autophagy inhibitors in tumor cells which enables significantly enhanced radiosensitization. The designed ZMC can precisely probe tumors via background-free fluorescence under the guidance of afterglow of high signal-to-noise ratio 50.7 which specifically enhanced by the tumor microenvironment (TME). Under X-ray irradiation, the tetrasulfide-incorporated mesoporous silica coating on the surface of afterglow nanoparticle undergoes cleavage, leading to rapid release of the autophagy inhibitors (50% released within 30 minutes). The efficient release is facilitated by a highly active redox-cleavage reaction between the tetrasulfide bonds and the abundant H 2 O 2 generated by X-ray excitation in the mildly acidic condition of TME. In animal models, the ZMC exhibit highly effective radiosensitization in hypopharyngeal carcinoma that is highly dependent on radiotherapy. This work overcomes the limitations of conventional drug delivery systems, such as off-target release and slow response (e.g., glutathione (GSH)-triggered release exceeding 6 hours), and offers a new strategy for precise and rapid delivery of autophagy inhibitors.