Beyond apoptosis: nanomedicine enabled reprogramming of tumor cell death for next-generation radiosensitization.

Radiotherapy remains a cornerstone in the clinical management of malignancies, leveraging DNA damage and oxidative stress to eradicate tumor cells. Nonetheless, the emergence of intrinsic and acquired radioresistance significantly compromises its therapeutic efficacy. While nanomedicine has substantially advanced radiosensitization strategies, the existing literature has largely focused on physical dose enhancement or conventional apoptosis, and the systematic reprogramming of diverse cell death modes beyond conventional apoptosis in the radiotherapy context has received less systematic attention. The present review provides a cross‑pathway synthesis of how engineered nanomaterials redirect tumor cell fate beyond apoptosis to achieve next‑generation radiosensitization, while also identifying the specific limitations and knowledge gaps that currently impede progress in this rapidly evolving field. We first delineate the hierarchical sensitization mechanisms, beginning with physical energy deposition via high-Z elements, followed by chemical amplification of reactive oxygen species through nanozyme catalysis, and biological intervention in the "6R" principles of radiobiology. Crucially, we evaluate the potential capacity of advanced nanomaterials to bypass conventional apoptotic resistance by triggering ferroptosis, pyroptosis, cuproptosis, disulfidptosis, and other emerging programmed death pathways, with a focus on the current evidence base and remaining preclinical and translational challenges. Beyond localized cytotoxicity, we highlight the mechanistic potential of nanomedicine to induce immunogenic cell death and activate the cGAS-STING pathway, suggesting a possible framework for transforming RT into an "in situ vaccine" that could reshape the immunosuppressive TME. Furthermore, we discuss the clinical translation of landmark nano-radiosensitizers, such as NBTXR3 and AGuIX, while critically addressing fundamental bottlenecks in targeting efficiency, biodistribution, and biosafety. By synthesizing current trends and future perspectives, this review contributes a strategic roadmap for advancing the design of next-generation, intelligent nanoplatforms toward more precise and systemic radiosensitization.