Precision Oncology via Radiotherapy-Triggered Drug Delivery: Mechanisms, Molecular Engineering, and Clinical Translation.

Radiotherapy-triggered drug delivery systems (RDDS) promise to integrate the spatial precision of ionizing radiation with controllable pharmacological activation. However, clinical translation remains constrained by its reliance on supra-clinical irradiation doses. Here, we present a unifying framework redefining RDDS through two distinct paradigms: structural disassembly and molecular actuation. We delineate their radiochemical foundations, highlighting reductive and electron-driven mechanisms as more robust and tumor-selective than stochastic reactive oxygen species-mediated pathways. Furthermore, we position radiation-driven gas therapy as a distinct modality based on in situ molecular generation. Critically, we identify the dose-response mismatch between radiolytic chemistry and clinical radiation as the central translational bottleneck. To overcome this, we propose a design paradigm centered on highly predictable, dose-matched activation, where mechanisms directly coupling radiation energy to molecular transformation offer superior predictability. Finally, we explore the integration of RDDS with imaging and artificial intelligence to create closed-loop, feedback-controlled systems. This review establishes a conceptual and translational roadmap, envisioning the evolution of radiotherapy from a purely cytotoxic modality into a programmable actuator for precision oncology.