Triple-Synergistic Mitochondria-Targeted NIR Fluorescent Probe for Mitochondrial Hydrogen Sulfide: Precision Monitoring and Image-Guided Resection of Metastatic Breast Cancer

Metastatic breast cancer (MBC) is the primary cause of breast cancer-related mortality, where mitochondrial H2S (Mito-H2S) serves as a key metastatic mediator. However, further understanding of Mito-H2S metabolism during metastasis remains limited, largely due to a lack of specific imaging probes. Additionally, the inherently low signal-to-noise (S/N) ratio of most fluorescent probes presents significant challenges for tumor localization and surgical resection. To address these, we developed an activatable near-infrared fluorescent probe (SCy-H2S) featuring triple-synergistic mitochondrial targeting: positive ζ-potential driven electrostatic interactions, high-affinity binding to membrane protein, and selective activation by Mito-H2S. Upon interaction with Mito-H2S, the probe exhibits a pronounced fluorescence turn-on, achieving a high S/N ratio for real-time tracking of Mito-H2S dynamics. Moreover, by exploiting the role of Mito-H2S, we elucidate the mechanistic relationship between Mito-H2S and mitochondrial ATP production during cancer progression. The probe successfully visualizes Mito-H2S upregulation during metformin-induced liver injury and breast cancer metastasis, enabling the accurate delineation of tumor margins for fluorescence-guided resection of liver metastases.