pH-responsive nanovesicles capable of remodeling the tumor microenvironment enable activatable near-infrared-II fluorescence image-guided enhanced radiotherapy

Traditional radiotherapy (RT) lacks the precision to distinguish between tumor and normal tissues, leading to inevitable X-ray-induced side effects in patients. Therefore, it is crucial to develop integrated imaging and therapeutic modalities that can reduce side effects on surrounding healthy tissues while enhancing susceptibility to tumor tissues. In this study, we developed a pH-responsive nanodrug (AuNRs-Mn₃O₄-Ag₂S Ve) by self-assembling the second near-infrared (NIR-II, 950-1700 nm) fluorescent probe Ag₂S quantum dots (QDs), multifunctional nanozyme Mn₃O₄ nanoparticles (NPs), and radiosensitizer gold nanorods (AuNRs) into a single nanoplatform <i>via</i> an emulsion process. This nanodrug enables precise tumor localization for accurately guided RT and multi-angle sensitization of RT. Upon intravenous administration, the nanodrug disintegrates in the tumor area due to the pH-sensitive polymer P4VP, releasing Ag₂S QDs which are specifically activated by the acidic environment, thereby "turning on" the NIR-II fluorescence signal. The optimal timing of the NIR-II fluorescence signal within the tumor region after intravenous injection was investigated, providing a reference for guided RT. <i>In vitro</i> and <i>in vivo</i> experiments confirmed the efficient enhancement of tumor radiosensitization by AuNRs and Mn₃O₄ NPs. The specific imaging modality that transitions the fluorescence signal from "off" to "on" has been successfully implemented, addressing the limitations of conventional RT and enhancing radiosensitivity. The integration of imaging and therapeutic approaches in this study presents a promising modality for image-guided tumor RT.