Radiation-enhanced self-cascade catalytic Ti3C2Tx-based platform enables controlled release of trans-resveratrol for synergistic radiosensitization against metastasis of orthotopic breast cancer

Synergistic radiosensitization of cancer cells by metal-based nanomaterials and natural products is a forward-looking alternative for radiotherapy enhancement while inhibiting tumor metastasis. This work explores a phase change material (PCM)-gated Ti 3 C 2 T x nanosheet as a photothermal-responsive drug delivery system for loading natural trans -resveratrol (RSV), aiming at such synergistic radiosensitization in a controlled manner. This system can improve the biodispersity of RSV in the physiological solutions and inhibit the radiation-enhanced enzymatic activity of Ti 3 C 2 T x nanosheets to a large extent. Upon 808 nm near infrared light illimitation, Ti 3 C 2 T x -mediated photothermal heating makes the loaded PCM to be melted, resulting in the controlled release of RSV and simultaneous recovery of radiation-enhanced enzymatic activity of Ti 3 C 2 T x nanosheets. By further irradiating with X-ray, Ti 3 C 2 T x nanosheets is responsible for enhanced catalytic decomposition of H 2 O 2 to highly toxic hydroxyl radical as well as the consumption of intracellular glutathione . Both in vitro and in vivo studies demonstrate that those excess radical oxygen species can synergize with the released RSV to induce cancer cell death by apoptosis/ferroptosis hybrid pathway, fully inhibiting growth and metastasis of orthotopic breast cancer. These results reveal that the combination of PCM-gated Ti 3 C 2 T x nanosheets with RSV is capable of fabricating the photothermal-responsive theranostic systems and aiding the confinement of synergistic radiosensitization exclusively in the cancer cells for radiotherapy enhancement against tumor metastasis.