Zirconium-engineered nanoplatform to enhance radiotherapy through NOD-like receptor-mediated pyroptosis.

e14595 Background: Radiotherapy faces significant challenges in clinical application due to tumor radioresistance and potential damage to normal tissues. While high-atomic-number nanomaterials show promise as radiosensitizers, their efficacy is often limited to physical dose enhancement without adequately addressing biological mechanisms. Methods: This study develops Zr-ATP nanoparticles through a coordination-driven self-assembly approach between zirconium ions and adenosine triphosphate, creating a biomimetic nanosystem for enhanced radio-immunotherapy. Results: The synthesized nanoparticles exhibit uniform spherical morphology with diameters below 100 nm and demonstrate excellent stability. In vitro studies reveal that Zr-ATP nanoparticles significantly enhance radiation-induced DNA damage and reactive oxygen species generation. Most importantly, the combination of Zr-ATP with radiotherapy simultaneously triggers both immunogenic cell death and pyroptosis, as evidenced by calreticulin exposure, HMGB1 translocation, and caspase-1 activation. Transcriptomic analysis confirms the activation of NOD-like receptor signaling pathway underlying these cell death mechanisms. In vivo evaluation demonstrates that Zr-ATP nanoparticles achieve effective tumor accumulation and, when combined with radiotherapy, significantly inhibit tumor growth while prolonging survival in melanoma-bearing mice. The treatment exhibits a favorable safety profile with minimal systemic toxicity. Conclusions: These findings establish Zr-ATP nanoparticles as a dual-function radiosensitizer that not only enhances physical radiation efficacy but also activates potent antitumor immunity through coordinated induction of immunogenic cell death and pyroptosis, offering a promising strategy for improving radiotherapy outcomes.