Phase‐Change Assembling Nanostructures Synergistically Potentiate Tumor Radiosensitivity by Reducing the Stemness of Cancer Stem‐Like Cells

ABSTRACT Cancer stem‐like cells (CSCs) within deep tumors are a fundamental contributor to radiotherapy (RT) resistance due to their pronounced stemness resulting in unique unlimited self‐renewal and differentiation capabilities. Alleviating hypoxic microenvironment of deep tumors to attenuate the stemness of CSCs remains a significant challenge, as the dense extracellular matrix (ECM) severely restricts oxygen diffusion into deep tumors. Herein, a nano‐delivery particle (AMPM) is constructed to improve ECM permeability for deep tumor oxygen and radiosensitizer delivery. Natural fatty acid low‐melting eutectic mixtures are employed as phase change materials (PCM) to encapsulate thermoresponsive self‐assembled micelles, O 2 pre‐saturated perfluoropentane, and nitroimidazole sensitizers (metronidazole, MTZ), with the goal of enhancing RT. Under 808 nm light irradiation, PCM acts as a temperature‐sensitive gatekeeper that undergoes solid‐to‐liquid phase transition under mild hyperthermic conditions (40°C), precisely controlling the release of MTZ and oxygen. Additionally, this design enhances the ECM permeability of the tumor, facilitating the delivery of oxygen and MTZ to deep‐seated tumors. In TNBC (triple‐negative breast cancer) mouse models, the combination of oxygen and MTZ effectively reverses radioresistance caused by hypoxic tumor microenvironment and CSCs, while significantly enhancing the efficacy of RT. Combination treatment with AMPM and RT (4 Gy) achieves a tumor inhibition rate of 91.2%, substantially surpassing high‐dose RT alone (12 Gy, 52.1% inhibition). This study presents an innovative sensitization strategy with considerable clinical application potential for radiosensitization.