Low Dose Soft X-Ray Remotely Triggered Lanthanide Nanovaccine for Deep Tissue CO Gas Release and Activation of Systemic Anti-Tumor Immunoresponse

Gas-based therapy has emerged as a new green therapy strategy for anti-tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X-ray-triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF₄:Gd,Tb@NaLuF₄) with photo-responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno-therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X-ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti-tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X-ray activated systemic anti-tumor immunoresponse. This work provides a new strategy of designing anti-tumor nanovaccines for synergistic deep tissue gas-therapy and remote soft X-ray photoactivation of the immune response.