GSH-Activatable Rare-Earth Nanoprobe for NIR-II Fluorescence Imaging-Guided Surgery and Enhanced Chemotherapy/Chemodynamic Therapy of Breast Cancer

The precise intraoperative delineation of tumor margins and the controlled intratumoral release of chemotherapeutic agents remain major challenges in breast cancer therapy. Tumor microenvironment (TME)-responsive nanoplatforms provide a promising approach by utilizing the distinctive biochemical properties of tumors to achieve targeted imaging and treatment. Herein, we developed a glutathione (GSH)-activatable theranostic nanoprobe (DSM-cRGD) emitting fluorescence in the second near-infrared window (NIR-II). The probe is constructed from Nd-doped rare-earth nanoparticles coated with a manganese dioxide (MnO 2 ) shell and functionalized with cyclic RGD peptide for α v β 3 -integrin targeting. The MnO 2 shell quenches NIR-II fluorescence during systemic circulation and undergoes GSH-responsive degradation within the TME. In addition, the nanoprobe shows strong targetability within tumors via specific binding to α v β 3, thereby enabling real-time, high-contrast surgical navigation. Moreover, a newly developed therapeutic agent, DSM-cRGD@DOX, formed by loading doxorubicin (DOX) onto DSM-cRGD, enables the simultaneous release of DOX and Mn 2+ ions upon degradation of the MnO 2 shell in the tumor microenvironment (TME), thereby inducing synergistic chemodynamic and chemotherapeutic effects. This further induces immunogenic cell death, activating anti-tumor immune responses and suppressing tumor recurrence and metastasis. Collectively, this DSM-cRGD-based platform represents an integrated nanoplatform that combines precise tumor imaging with stimuli-responsive drug delivery, offering an advanced strategy for the precision management of breast cancer.