A photothermal-responsive multi-enzyme nanoprobe for ROS amplification and glutathione depletion to enhance ferroptosis.

Ferroptosis therapy employs reactive oxygen species (ROS) generated via Fenton or Fenton-like reactions. However, the antioxidant system associated with the tumor microenvironment (TME) exhibits high levels of glutathione (GSH) that significantly restrict the therapeutic efficacy of ferroptosis. In this study, we propose a near-infrared (NIR)-responsive hollow mesoporous manganese dioxide (HM-MnO2) nanoprobe with multi-enzyme-like activity for enhanced ROS generation and GSH depletion that can efficiently promote ferroptosis. The ferroptosis inducer RSL3 is encapsulated within HM-MnO2 with a loading capacity of 67 %, while iron-doped dopamine (Fe-PDA) and cRGD tumor-targeting peptides are conjugated on the surface. The resultant MnO2R@FePDA-cRGD nanocomposite delivers a photothermal conversion efficiency of 39.1 % under 808 nm irradiation, which can effectively trigger structural degradation of the nanoplatform and the rapid release of RSL3. The photothermal effects significantly augment catalytic activity, enabling a multi-enzyme mimicking that includes peroxidase (POD), oxidase (OXD), GSH peroxidase (GPx), and NADH oxidase (NOx) functions, generating significant ROS radicals and an efficient depletion of intracellular GSH. These cascade reactions contribute to an optimal TME for inducing "explosive" ferroptosis with a synergistic inhibition of tumor growth in vitro and in vivo. The proposed strategy represents a potent approach to amplifying ferroptosis through the photothermal-driven rapid release of RSL3 and enhanced multi-enzyme mimetic activities with significant potential in nanomedicine-based cancer therapy.