A dual-channel electron expressway triggers piezocatalytic ferroptosis–mitochondrial catastrophe cascade for anti-glioblastoma therapy

Glioblastoma (GBM) remains clinically challenging due to its pronounced resistance to conventional chemotherapy. Ferroptosis, an iron-dependent form of programmed cell death, has emerged as a promising alternative, yet its efficacy is limited by the hypoxic tumor microenvironment and adaptive mitochondrial defenses. To overcome these limitations, we developed a piezoelectric nanoplatform (V-BT@PDA@PMS) comprising double-vacancy-engineered barium titanate (BaTiO 3 ) nanoparticles, coated with polydopamine (PDA), and loaded with peroxymonosulfate (PMS). This platform constructs a “Dual-Channel Electron Expressway” to significantly amplify ultrasound (US)-triggered generation of sulfate radicals (⋅SO 4 − ). Internally, barium and oxygen vacancies within the BaTiO 3 lattice facilitate charge carrier separation; externally, the tumor-acid-responsive PDA coating optimizes PMS adsorption and activation via imino protonation. The resulting massive ⋅SO 4 − yield exerts a dual-pronged effect: it directly initiates lipid peroxidation to drive ferroptosis and precipitates intracellular Ca 2+ as CaSO 4 . This localized Ca 2+ depletion triggers profound mitochondrial Ca 2+ efflux and the irreversible opening of the mitochondrial permeability transition pore (mPTP). The subsequent structural collapse facilitates a secondary iron influx, establishing a self-amplifying cycle of reactive oxygen species (ROS) generation via Fenton-like reactions. By systematically dismantling mitochondrial defenses against ferroptosis, this cascade achieves a 2.9-fold enhancement in temozolomide (TMZ) chemosensitivity in vitro and demonstrates significant tumor inhibition in chemoresistant in vivo models. Overall, this study elucidates a physical-biochemical mechanism for electron-transport-mediated mitochondrial destabilization, offering a rational design strategy for piezocatalytic nanotherapeutics against drug-resistant malignancies.