Acid and Hypoxia Tandem‐Activatable Deep Near‐Infrared Nanoprobe for Two‐Step Signal Amplification and Early Detection of Cancer

Abstract The early detection of cancers can significantly change outcomes even with existing treatments. However, ~50% of cancers still cannot be detected until they reach an advanced stage, highlighting the great challenges in the early detection. Here, an ultrasensitive deep near‐infrared (dNIR) nanoprobe that is successively responsive to tumor acidity and hypoxia is reported. It is demonstrated that the new nanoprobe specifically detects tumor hypoxia microenvironment based on deep NIR imaging in ten different types of tumor models using cancer cell lines and patient‐tissue derived xenograft tumors. By combining the acidity and hypoxia specific two‐step signal amplification with a deep NIR detection, the reported nanoprobe enables the ultrasensitive visualization of hundreds of tumor cells or small tumors with a size of 260 µm in whole‐body imaging or 115 µm metastatic lesions in lung imaging. As a result, it reveals that tumor hypoxia can occur as early as the lesions contain only several hundred cancer cells.