A self-assembled fluorescent contrast agent for imaging-guided simultaneous resection of breast tumors and metastatic lymph nodes in surgery.

Accurate intraoperative margin assessment and reliable detection of metastatic sentinel lymph nodes (SLNs) remain critical challenges in breast cancer surgery. We developed sa-FCA, a novel XIAP-targeting near-infrared fluorescent probe that achieves enhanced tumor specificity and sensitivity, along with a prolonged imaging window, via tumor-selective cascade activation and in situ self-assembled nanostructures. In a mouse model of breast cancer, sa-FCA demonstrated precise tumor localization, sensitive detection of metastatic SLNs, and identification of spontaneous pulmonary metastases. Clinical evaluation using human specimens showed excellent discrimination between tumor and benign tissues such as fibroadenoma (n = 252 patients, 99.59% sensitivity and 97.37% specificity), with clear lesion delineation. Furthermore, it accurately distinguished between metastatic and non-metastatic SLNs, with a sensitivity of 98.18% and a specificity of 92.31% (n = 69). By significantly improving metastatic SLN detection, sa-FCA overcomes the intraoperative diagnostic delays inherent in conventional pathology and facilitates immediate surgical decision-making. The ability of sa-FCA to precisely target tumors, differentiate fibroadenoma, and identify metastatic nodes allows for complete tumor resection with maximal normal tissue preservation, thereby enhancing both oncological safety and cosmetic outcomes. These findings establish a new paradigm for image-guided breast cancer surgery and promote the clinical translation of fluorescence-guided interventions.