Natural killer cell-inspired dendritic mesoporous rare-earth nanoparticles potentiate X-ray-triggered reactive oxygen generation for low-dose radiotherapy-radiodynamic therapy

The efficacy of traditional radiotherapy has been significantly limited by its severe side effects, tumor hypoxia, and insufficient tumor accumulation. To address these challenges, we developed a multifarious radio enhancer composed of NK cell-derived extracellular vesicle (NKEV)-cloaked dendritic mesoporous thulium oxide (Tm 2 O 3 ) encapsulated with cerium clusters (Ce 6 C)-photosensitizer (TSSI) coordination (TSSI-Ce 6 C-DMTm@NKEV). This nanoplatform is designed to heighten X-ray absorption and energy transfer while generating oxygen to alleviate tumor hypoxia, thereby improving radiotherapy-radiodynamic therapy. Once accumulated at tumor sites, the TSSI-Ce 6 C-DMTm@NKEV nanoparticles could actively recognize the tumor cells and then catalyze endogenous hydrogen peroxide (H 2 O 2 ) to produce oxygen, thereby increasing oxygen supply and alleviating tumor hypoxia. Upon X-ray irradiation, the nanoparticles could significantly enhance hydroxyl radical (•OH) generation from Ce 6 C-DMTm for high-efficiency radiotherapy via matching between Tm's K-edge with X-ray bremsstrahlung peak, and synchronously facilitate singlet oxygen ( 1 O 2 ) generation from adjacently coordinated TSSI for radiodynamic therapy. This dual mechanism of action, integrated with the alleviation of tumor hypoxia, leads to superior anticancer outcomes through lipid peroxidation, mitochondrial dysfunction, and DNA double-strand break. Our work demonstrates a potential radiotherapy strategy that leverages low-dose X-ray to intensify tumor suppression while minimizing systemic toxicity. The TSSI-Ce 6 C-DMTm@NKEV nanoparticles can actively recognize tumor cells and then catalyze endogenous hydrogen peroxide to produce oxygen, thereby alleviating tumor hypoxia. Then, upon X-ray irradiation, the nanoparticles would enhance hydroxyl radical generation from Ce 6 C-DMTm for radiotherapy and simultaneously facilitate singlet oxygen generation from adjacently coordinated TSSI for radiodynamic therapy, thereby exhibiting optimal antitumor efficacy. • This nanoplatform could heighten X-ray absorption and energy transfer while generating oxygen to alleviate tumor hypoxia. • Upon X-ray irradiation, the nanoparticles could enhance •OH and 1 O 2 generation for radiotherapy-radiodynamic therapy. • Ce 6 C-photosensitizer coordination could function as a radiosensitizer, a radiodynamic agent, and an oxygen generator. • Functionalization with NKEV improves the biosafety and tumor-targeting capability of the nanosystem.