A photothermal-promoted cascade nanozyme to enhance hydroxyl radical/nitric oxide generation for reactive oxygen species-modulated catalytic/gas therapy

Reactive oxygen species (ROS) are critical in tumor therapy, but the antioxidant tumor microenvironment severely restricts the ROS-modulated antitumor efficacy. In this study, a photothermal-promoted cascade nanozyme (MnO 2 @Lap/PAH/L-Arg@Au) was constructed by modifying β-lapachone (β-Lap), poly(allylamine hydrochloride) (PAH), and L-arginine (L-Arg) and depositing gold nanoparticles (AuNPs) on hollow manganese dioxide (MnO 2 ), enhancing ROS-modulated catalytic/gas combination therapy. The pH- and glutathione-responsive hollow MnO 2 degradation released β-Lap to elevate the generation of hydrogen peroxide (H 2 O 2 ), which substantially activated and AuNPs-mediated hydroxyl radical (·OH) generation. Moreover, H 2 O 2 /·OH induces L-Arg to produce highly toxic nitric oxide (NO), and the Au nanoshell with high photothermal conversion efficiency (38.6 %) further enhanced ROS/NO generation. By reducing adenosine triphosphate production and inducing mitochondrial dysfunction, the combination of photothermal/catalytic/gas therapy greatly triggered cell apoptosis and inhibited tumor growth. Thus, the developed MnO 2 @Lap/PAH/L-Arg@Au nanozyme established a dynamic cascade pathway of “ROS-driven NO release”, and achieved photothermal-promoted catalytic/gas therapy.