Holographically Activatable Nanoprobe via Glutathione/Albumin‐Mediated Exponential Signal Amplification for High‐Contrast Tumor Imaging
Ting Li, Shuangxiu Tan, Mengjuan Li, Jie Luo, Yueyue Zhang, Zhen Jiang, Yibin Deng, Liang Han, Hengte Ke, Junkang Shen, Yongan Tang, Fan Liu, Huabing Chen, Tao Yang
Abstract
Abstract Glutathione (GSH)‐activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non‐selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor‐selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin‐mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn 2+ with threshold GSH concentration of ≈ 0.12 m m for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH‐relevant cisplatin resistance during chemotherapy. Upon efficient up‐regulation of extracellular GSH in tumor via exogenous injection, the relaxivity‐silent interstitial nanoprobe remarkably evolves into Mn 2+ that are further captured/retained and re‐activated into ultrahigh‐relaxivity‐capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off‐targeted nanoprobe in the form of Mn 2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin‐mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.