Lutetium‐Based Nanoprobes for Radiosensitization with Immune Microenvironment Remodeling and NIR‐II Fluorescence Imaging‐Guided Surgery in Colorectal Cancer

Abstract Colorectal cancer (CRC) is among the top five leading cancers worldwide. Preoperative concurrent chemoradiotherapy is recommended for locally advanced CRC. Radiotherapy (RT), a traditional cancer treatment, not only controls local tumor growth but also potentially induces immunogenic cell death, initiating systemic immune responses. Given the poor radiosensitivity of CRC, improving RT sensitization is a critical unmet need. Despite advances in intraoperative imaging, achieving complete resection of colorectal tumors with clear margins in real time remains a significant clinical challenge. This study introduces RVLu@ICG, a novel multifunctional fluorescent nanoprobe emitting in the second near‐infrared (NIR‐II) range. It's demonstrated that RVLu@ICG has tumor‐specific targeting due to modification with cyclic arginine‐glycine‐aspartic acid (c(RGDfK)) pentapeptide and induces augmented reactive oxygen species (ROS) production under ionizing radiation exposure. This synergistic mechanism not only potentiates radiosensitization efficacy but also facilitates radiation‐induced remodeling of the tumor immune microenvironment. Additionally, NIR‐II fluorescence image guidance facilitates precise surgical navigation in microtumor models, intramuscular tumor invasion models, and peritoneal metastasis models. Notably, the nanoprobe demonstrates excellent biocompatibility both in vitro and in vivo. Thus, RVLu@ICG establishes a robust precision therapy platform for the treatment of CRC.