“AND” Logic‐Gated MRI Nanoswitch in Response to Copper and Glutathione for Precise Diagnosis of Microtumors

ABSTRACT “Always‐on” MRI nanoprobe easily generates artifact signal due to non‐specific interaction with tumor, resulting in inaccurate diagnosis. Stimulus‐responsive nanoswitch can specifically amplify tumor signal and decrease background signal, improving diagnostic efficacy of the tumor. However, single stimulus for tumor specificity is often insufficient, which is prone to interference and leads to off‐target effects. Herein, Cu and GSH “AND” logic‐gated responsive nanoswitch (cRGD‐dsESIONP) was developed by the conjugation of disulfide bonds between cRGD cyclopeptide and ESIONP. For tumors within only high GSH expression, the disulfide bonds on the surface of cRGD‐dsESIONP were cleaved by GSH, but cRGD‐dsESIONP cannot assembly into aggregates and still exhibited T 1 contrast imaging. However, for the tumors within high GSH and Cu expression, the cRGD‐dsESIONP was cleaved into ESIONP‐SH by GSH, subsequent ESIONP‐SH captured intracellular Cu and assembled into aggregates, which resulted in switching from T 1 contrast imaging to T 2 contrast imaging, then enlarged tissue signal‐to‐noise ratio, and accurately diagnosed tumors. In vivo experimental results demonstrated that cRGD‐dsESIONP had excellent biocompatibility and enabled precise imaging for microtumors within high Cu and GSH expressions. The design of logic‐gated nanoswitch in response to GSH and Cu provides a novel approach for accurate MRI diagnosis of microtumors.