Single-dose X-ray driven persistent activation of nanoprodrugs for radio-chemo-immunotherapy

X-ray triggered local activation of prodrugs is promising for tumor radio-chemo-immunotherapy. However, the insufficient active drugs within tumors under prescribed X-ray doses lead to poor immunogenic effects. Here, we proposed to develop ClO^--responsive nanoprodrug (DOX/S-M) that could persistently release DOX in response to inflammation induced by single-dose X-ray irradiation, thereby maintaining high levels of active DOX in tumors. DOX/S-M, prepared by the self-assembly of DOX-S-mPEG₂₀₀₀ and tumor-targeting amphiphilic polymers (DSPE-PEG-Folate), were stable in normal environments. After X-ray irradiation, DOX/S-M, which was accumulated at the tumor site in a targeted manner for 24 h, underwent collapse and DOX release for 24 h in the presence of a high concentration of ClO^- produced by the infiltration and activation of inflammatory cells. Consequently, DOX/S-M induced systemical immune responses through activating strong immunogenic cell death (ICD) following X-ray irradiation, exhibiting significant inhibition of both primary and distant tumors. Meanwhile, DOX/S-M showed negligible toxicity to normal tissues. In a word, this work developed an X-ray stimuli prodrug activation strategy for tumor radio-chemo-immunotherapy that utilizes X-ray triggered inflammatory response in tumors for controlled and persistent chemotherapeutic drugs activation, providing valuable guidance for exploring clinical anti-cancer strategy with low toxicity and high therapeutic efficacy.