Glutathione-Priming Nanoreactors Enable Fluorophore Core/Shell Transition for Precision Cancer Imaging

In an attempt to develop an imaging probe with ultra-high sensitivity for a broad range of tumors in vivo and inspired by the concept of chemical synthetic nanoreactors, we designed a type of glutathione-priming fluorescent nanoreactor (GPN) with an albumin-coating shell and hydrophobic polymer core containing disulfide bonds, protonatable blocks, and indocyanine green (ICG), a near-infrared fluorophore. The albumin played multiple roles including biocompatible carriers, hydrophilic stabilizer, "receptor" of the fluorophores, and even targeting molecules. The protonation of the hydrophobic core triggered the outside-to-core transport of acidic glutathione (GSH), as well as the core-to-shell transference of ICGs after the disulfide bond cleavage by GSH, which induced strong binding of fluorophores with albumins on the GPN shell, initiating intensive fluorescence signals. As a result, the GPNs demonstrated extremely high response sensitivity and imaging contrast, proper time window, and broad cancer specificity. In fact, an orthogonal activation pattern was found in vitro with an ON/OFF ratio up to 24.7-fold. Furthermore, the nanoprobes specifically amplified the tumor signals in five cancer-bearing mouse models and actualized tumor margin delineation with a contrast up to 20-fold, demonstrating much better imaging efficacy than the other four commercially available probes. Therefore, the GPNs provide a new paradigm in developing high-performance bioresponsive nanoprobes.