Cu²⁺-Mediated Cascade-Responsive Nanodiamond-Based Platform Triggering Redox Dyshomeostasis for Cancer-Specific Chemo/Chemodynamic Combination Therapy

The redox homeostasis in tumor cells is an innate defense barrier for reactive oxygen species (ROS)-mediated tumor therapy. Herein, an intratumoral cascade-responsive multifunctional nanodiamond-based platform (NPCD) with a hydrodynamic diameter of 191 ± 5 nm triggering redox dyshomeostasis is fabricated by Cu2+-mediated coordination for polylysinated nanodiamond and doxorubicin (DOX) to achieve cancer-specific diagnosis and therapy. The NPCD nanoplatform enables precise tumor fluorescence localization and chemotherapy through a “turn on” effect due to being specifically activated by GSH to trigger DOX release at a low-pH tumor-specific environment instead of normal cells. Furthermore, NPCD realizes Cu+-based chemodynamic therapy (CDT) and induces GSH depletion by Cu2+ reduction to support CDT. These cause intracellular redox dyshomeostasis, making tumor cells more sensitive to the NPCD nanoparticles. Additionally, NPCD also possesses the intrinsic ability to reverse drug resistance. Of note, NPCD mainly accumulates in the tumor site in 4T1 tumor-bearing mice and enhances the efficacy of therapeutic interventions with negligible side effects. More interestingly, combined with programmed cell death ligand 1 antibody (anti-PD-L1) and imiquimod (R837), NPCD significantly suppresses distant tumor growth, indicating a good immune response. Therefore, this work opens perspectives for the further development of synergistic therapy through a Cu2+-mediated intratumoral cascade reaction.