Full-process radiosensitization, that is, pre-increasing radiation sensitivity of cancer cells, magnifying •OH formation during ionizing irradiation, and intervention on the resultant DNA repair for final cells death, could enhance the overall radiotherapeutic effects, but has not yet been achieved. Herein, Hf-nMOFs with Fe3+ ions uniformly dispersed (Hf-BPY-Fe) were constructed to integratedly improve radiotherapeutic effects via a multifaceted mechanism. The in vitro experiments demonstrated that persistent reactive oxygen species stress from Hf-BPY-Fe-activated in situ Fenton reaction reassorted cell cycle distribution, consequently contributing to increased tumoral radiosensitivity to photon radiation. Upon irradiation during the course of radiation therapy, Hf4+ in Hf-BPY-Fe gave substantial amounts of high-energy electrons, which partially converted H2O to •OH and, meanwhile, relaxed to a low-energy state in nMOF pores, leading to an electron-rich environment. These aggregated electrons facilitated the reduction from Fe3+ to Fe2+ and further promoted the production of •OH in the Fenton process to attack DNA. The Hf-BPY-Fe postponed the DNA damage response process by interfering with certain proteins involved in the DNA repair signaling pathway. The in vivo experiments showed improved radiotherapeutic effects from integrated contributions from Fe3+-based Fenton reaction and Hf4+-induced X-ray energy conversion in tumors. This work provides a nMOFs-based full-process radiosensitizing approach for better radiotherapeutic efficacy.
Keywords: chemodynamic therapy; full-process radiosensitization; hydroxyl radicals; metal−organic frameworks; radiotherapy.