Spatiotemporal Mapping of Lymphatic Metastases in Gastric Cancer Using Tumor-Trackable and Enzyme-Activatable Near-Infrared Fluorescent Nanoprobes

Sentinel lymph node biopsy holds significant importance in cancer management, yet the challenge persists in early detection and precise resection of metastasis lymph nodes (LNs) due to the absence of specific and sensitive optical probes. This study reports metastatic LN reporters (MLRs) with an activatable optical output for accurate spatiotemporal mapping of lymphatic metastases in gastric cancer. MLRs are self-assembled entities incorporating mixed amphiphiles with a lipophilic tail and a tumor-targeting ligand or a fluorescent moiety that is caged with a switch cleavable by tumor-specific β-galactosidase (β-Gal). After draining into LNs, MLRs selectively activate their near-infrared fluorescence in the presence of spreading tumor cells. In orthotopic gastric cancer mouse models, the representative reporter MLR1 distinguishes macro/micrometastatic LNs from benign LNs and enables early detection of skip LNs metastasis patterns in a spatial-dependent manner. Such an active sensing mechanism provides a high level of sensitivity and specificity comparable to those of flow cytometry analysis. In surgically resected patient specimens, MLR1 differentiates cancerous tissues and metastatic LNs from normal tissues and benign LNs within 1 h. This study thus presents NIRF nanoprobes that permit facile detection of LN metastases in GC patient samples and highlights a generic translatable nanoprobe design for understanding metastatic progression.