Integrating Biological and Physical Principles of Next‐Generation Radiotherapy to Fabricate Engineered Nanoplatforms for Improving Radiotherapy Efficacy

Nanomedicine has significantly improved the efficacy of radiotherapy (RT) by facilitating controlled delivery, enhancing radiosensitivity, and modulating tumor hypoxia and heterogeneous radiation responses while managing toxicity in normal tissues. However, emerging next‐generation RT modalities, including ultrahigh‐dose‐rate FLASH RT, proton and heavy‐ion RT characterized by Bragg peak‐guided dose localization and high linear energy transfer (LET), magnetic resonance‐guided adaptive RT (MRgRT), spatially fractionated RT (SFRT) featuring spatiotemporal dose heterogeneity, and stereotactic body RT (SBRT), have introduced unique dose‐rate and LET distributions, as well as spatiotemporal dose structures. These innovative physical properties produce novel biological outcomes, creating conceptual space for the neofunctionalization of nanoplatforms and their integration with other promising therapies. Herein, the biological and physical principles of RT are described, followed by a summary of current advances in nanoplatforms, their mechanisms, and potential combination strategies for emerging RT modalities, relevant dosimetry considerations, and preclinical and translational research. Overall, this review establishes a comprehensive framework that links engineered nanoplatforms to the physical and biological characteristics of next‐generation RT, providing a conceptual and practical foundation for rational material development and clinical translation.