Doping Engineering to Modulate Lattice and Electronic Structure for Enhanced Piezocatalytic Therapy and Ferroptosis

Abstract Piezocatalytic therapy, which generates reactive oxygen species (ROS) under mechanical force, has garnered extensive attention for its use in cancer therapy owing to its deep tissue penetration depth and less O 2 ‐dependence. However, the piezocatalytic therapeutic efficiency is limited owing to the poor piezoresponse, low separation of electron–hole pairs, and complicated tumor microenvironment (TME). Herein, a biodegradable, porous Mn‐doped ZnO (Mn–ZnO) nanocluster with enhanced piezoelectric effect is constructed via doping engineering. Mn‐doping not only induces lattice distortion to increase polarization but also creates rich oxygen vacancies (O V ) for suppressing the recombination of electron–hole pairs, leading to high‐efficiency generation of ROS under ultrasound irradiation. Moreover, Mn‐doped ZnO shows TME‐responsive multienzyme‐mimicking activity and glutathione (GSH) depletion ability owing to the mixed valence of Mn (II/III), further aggravating oxidative stress. Density functional theory calculations show that Mn‐doping can improve the piezocatalytic performance and enzyme activity of Mn–ZnO due to the presence of O V . Benefiting from the boosting of ROS generation and GSH depletion ability, Mn–ZnO can significantly accelerate the accumulation of lipid peroxide and inactivate glutathione peroxidase 4 (GPX4) to induce ferroptosis. The work may provide new guidance for exploring novel piezoelectric sonosensitizers for tumor therapy.