Multimodal synergistic effects and theranostic integration of hafnium-based nanoradiosensitizers for enhancing precision radiotherapy.

Radiotherapy remains a cornerstone in oncology, yet its efficacy is limited by tumor radioresistance and off-target toxicity. This review elucidates the transformative potential of hafnium (Hf)-based radiosensitizers in overcoming these challenges. Leveraging Hf's high atomic number, these Hf-based biomaterials enhance X-ray energy deposition through photoelectric and Auger effects, generate cytotoxic reactive oxygen species (ROS), and modulate immunosuppressive tumor microenvironments to enhance radiotherapy effect. Their distinctive capability to achieve multimodal synergy by integrating radiotherapy with photodynamic, chemotherapeutic, or immunotherapeutic strategies enables precise targeting and significantly enhances antitumor responses. Subsequently, this review rigorously assessed the current synthetic methodologies for Hf-based radiosensitizers, along with their capacities and limitations in terms of controlling material properties and ensuring scalability. Advanced imaging modalities such as fluorescence, CT, SPECT, MRI, and PA further establish Hf-based systems as theranostic platforms for real-time tumor localization and treatment monitoring. While clinical candidates like NBTXR3 exhibit promising trial outcomes, challenges remain in mechanistic clarification, biocompatibility optimization, and controlled in vivo degradation. Emerging AI-driven design and multidisciplinary integration hold promise to expedite clinical translation, advancing Hf-based radiosensitizers toward intelligent, personalized cancer therapy paradigms. This work highlights Hf's critical role in redefining precision radiotherapy and delineates a roadmap for next-generation oncological intervention.