Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging.

Glutathione-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular glutathione (GSH) enrichment and uncontrollable background noise. Here, we show a holographically activatable nanoprobe caging manganese tetraoxide for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumor 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 mM 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 at 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. This article is protected by copyright. All rights reserved.