Core-shell Au@HOF nanoradiosensitizers activate potent immunogenic cell death for enhanced radio–radiodynamic–immunotherapy

Radiotherapy (RT) efficacy is constrained by inefficient radiation utilization and inadequate systemic immunity. Although nanoparticle-based radiosensitizers aim to enhance therapeutic outcomes, most existing systems lack effective integration of radiation enhancement, dynamic therapy, and systemic immune activation. Herein, we report Au@HOF, a core-shell nanoradiosensitizer synthesized via a facile one-pot strategy, comprising a gold core and a porphyrin-based hydrogen-bonded organic framework (HOF) shell. This unique architecture enables synergistic radio-radiodynamic therapy (RT-RDT) and robust immunogenic cell death (ICD) activation. The gold core enhances radiosensitization through efficient X-ray absorption and secondary electron emission in RT, while concurrently acting as a scintillator to activate the porphyrinic HOF shell for potent singlet oxygen (¹O₂) generation during RDT. The resulting RT-RDT synergy significantly amplifies reactive oxygen species production, intensifying oxidative stress to trigger potent ICD. This ICD cascade remodels the immunosuppressive tumor microenvironment, promoting T-cell infiltration and enhancing cancer immunotherapy. When combined with immune checkpoint blockade, Au@HOF elicits strong abscopal effects, suppressing both primary and metastatic tumors. Furthermore, Au@HOF serves as an effective contrast agent for computed tomography-guided tumor localization and radiation dose planning. Collectively, Au@HOF represents a precision nanoplatform that intelligently integrates enhanced RT-RDT with ICD-driven systemic antitumor immunity, providing a transformative strategy against advanced malignancies.