Tumor-targeting Cu2+/IR820-rich nanozymes to exert photothermal-reinforced reactive oxygen species production and dual glutathione scavenging for synergistic cancer therapy.

Despite the remarkable progress in reactive oxygen species (ROS)-mediated tumor treatment based on catalytic therapy and photodynamic therapy, the high intracellular glutathione (GSH) level, low Fenton reaction efficacy, and poor tumor targeting of small-molecule photosensitizers largely restrict the ROS-based antitumor effect. To overcome these challenges in better tumor treatment, versatile tumor-targeting nanozymes capable of conducting photothermal-reinforced GSH consumption and ROS production were fabricated through the incorporation of Cu2+ ions and IR820 with hyaluronic acid (HA)-decorated polydopamine (PDA) nanoparticles. The resulting HA-coated Cu2+/IR820@PDA (HCIP) nanozymes exhibited a solid-like spherical shape, sound colloidal dispersion, acid-activated Cu2+ and IR820 release. These nanozymes not only showed outstanding photothermal conversion efficiency (42.5 %), photothermal-enhanced PDA/Cu2+-elicited dual-mode GSH depletion and Cu2+-mediated hydroxyl radical (･OH) production, but also produced sufficient singlet oxygen (1O2) via IR820-based photodynamic effect. After being internalized by CT26 colon cancer cells via CD44-mediated endocytosis, the HCIP nanozymes efficiently depleted endogenous GSH and generated massive ROS comprising ･OH and 1O2 as well as hyperthermia under near-infrared (NIR) laser irradiation, thereby promoting apoptosis and ferroptosis via mitochondrial damage and lipid peroxidation. Notably, the in vivo studies showed that the HCIP nanozymes effectively accumulated at the CT26 tumor sites and inhibited tumor growth and splenomegaly upon photothermal-boosted ROS-mediated anticancer efficacy combined with ferroptosis without severe side effects. This work provides a new strategy for the design of dual-mode GSH-depleting and ROS-producing nanozymes to realize synergistic tumor treatment.