Gallic acid/copper ion-based metal-phenolic networks as photothermal-enhanced nanocatalysts for cancer therapy

Tumor microenvironment-responsive nanocatalysts enhance reactive oxygen species (ROS) accumulation by compromising tumor antioxidant defenses, offering a promising cancer treatment strategy. Leveraging the catalytic potential of metal-phenolic networks (MPNs), this study constructed GA-Cu MPNs as multifunctional carriers. Since endogenous catalase (CAT) limits hydrogen peroxide (H₂O₂) accumulation, the CAT inhibitor 3-amino-1,2,4-triazole was encapsulated within the MPNs to form GA-Cu-AT, which was further modified with hyaluronic acid to produce GA-Cu-AT@HA. GA-Cu-AT@HA converts superoxide anions to H₂O₂, which is further transformed into toxic hydroxyl radicals through peroxidase-like activity, while inhibits endogenous CAT to amplify oxidative stress. Under 808 nm NIR light, it exhibits photothermal activity, enabling synergistic photothermal-catalytic effects. <em>In vitro</em>, it induces ROS accumulation, mitochondrial damage, apoptosis, and immunogenic cell death (ICD). In in situ hepatocellular carcinoma, GA-Cu-AT@HA effectively suppresses tumor growth, induces apoptosis, and enhances damage-associated molecular patterns release <em>via</em> targeted accumulation. In 4T1 breast cancer xenografts, photothermal therapy enhances the infiltration of CD8⁺ T cells into tumors, promotes dendritic cell maturation, and elicits systemic CD8⁺ T cell responses, and reduces regulatory T cells. This tripartite strategy, encompassing oxidative cytotoxicity, ICD activation, and immune microenvironment remodeling, offers a novel approach for tumor redox regulation therapy.