Tannic Acid-Copper Coordination Gel-Coated Mesoporous Cuprous Oxide Nanoplatform for Synergistic 5-FU Chemotherapy and Enhanced Chemodynamic Therapy

To address the limitations of the tumor microenvironment (TME) and the inadequate efficacy of standalone chemodynamic therapy (CDT), this study developed a tannic acid-copper coordination gel-coated mesoporous Cu2O nanodelivery system (Cu2O@TA@5-FU) for synergistic enhanced CDT and chemotherapy. The system exhibits a high specific surface area (98 m2·g−1) and mesoporosity, achieving a 5-fluorouracil (5-FU) loading efficiency of 46.2%. Under simulated TME conditions, the nanodelivery system displayed markedly accelerated drug release and enhanced catalytic activity, indicative of pronounced TME responsiveness. In vitro, the Cu2O@TA support efficiently catalyzed a Fenton-like reaction with H2O2 to generate cytotoxic hydroxyl radicals (·OH) while depleting overexpressed intracellular GSH, thereby disrupting antioxidant defenses and amplifying oxidative stress. Combined with the antiproliferative action of released 5-FU, the synergistic treatment reduced 4T1 cell viability to approximately 23%, accompanied by sharp declines in intracellular ATP and GSH levels. This work overcomes the systemic toxicity of free 5-FU and the instability of Cu2O by employing a protective and stimuli-responsive TA-Cu coordination gel shell, offering a reliable strategy for TME-responsive synergistic nanotherapeutics that disrupt tumor metabolic and redox homeostasis.