An Intelligent Cupreous Nanoplatform with Self-Supplied H2O2 and Cu2+/Cu+ Conversion to Boost Cuproptosis and Chemodynamic Combined Therapy

Cuproptosis is a newly identified copper-dependent cell death and holds great promise for cancer therapy. However, transporting enough copper into cancer cells is a challenge. Herein, an intelligent cupreous nanoplatform (denoted as CuO2-MSN@TA-Cu2+), consisting of in situ formation of CuO2 within mesoporous silica nanoparticles (MSN) and then deposition with a tannic acid (TA)-Cu2+ complex, is designed and developed to realize on-demand copper delivery for cuproptosis-based combination therapy. CuO2-MSN@TA-Cu2+ exhibits tumor microenvironment-triggered therapeutic activity, wherein the outer TA-Cu2+ complex is readily disassembled to release Cu2+ and liberate the internal CuO2 to produce Cu2+ and H2O2. The overloaded Cu2+ can not only directly convert endogenous H2O2 and self-supplied H2O2 into highly toxic hydroxyl radicals for chemodynamic therapy (CDT) via Cu-based Fenton-like reaction but also undergo glutathione-mediated reduction into Cu+ species to induce potent cellular cuproptosis and enhance CDT. The experimental results indicate that CuO2-MSN@TA-Cu2+ produces remarkable cytotoxicity against cancer cells and significantly suppresses tumor growth by 93.42% in mice-bearing 4T1 breast tumors. This work provides a new paradigm to boost cuproptosis-related therapy and may also inspire the design of advanced therapeutic nanoplatforms.