Metabolic Acidity/H2O2 Dual‐Cascade‐Activatable Molecular Imaging Platform Toward Metastatic Breast Tumor Malignancy

Abstract Fluorescence imaging in the second near‐infrared window (NIR‐II) is crucial for accurate tumor diagnosis, offering superior resolution and penetration capabilities. Current NIR‐II probes are limited by either being “always on” or responding to one stimulus, leading to low signal‐to‐noise ratios and potential false positives. We introduced a dual‐lock‐controlled probe, HN‐PBA , activated by both H 2 O 2 and tumor acidic environment. This dual response ensures bright fluorescence at tumor sites, leading to higher tumor‐to‐normal tissue ratios (T/NT) compared to conventional “always on” probes and probes activated only by H 2 O 2 . This strategy allows precise tumor identification and removal of primary and metastatic tumors, achieving superior T/NT ratios (24.3/6.4 for orthotopic and lung metastasis, respectively). Our probe also effectively detected lung metastatic foci as small as≤0.7 mm and showed the capability for accurate lesion localization in clinical breast cancer specimens. This dual‐stimuli‐responsive strategy could aid future diagnostic probe design.