Lattice Distortion-Mediated Synergistic Piezoelectric–Long-Acting Chemodynamic Tumor Therapy via Ferroptosis with Cation-Doped Bismuth Nanospheres

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) and chemodynamic therapy (CDT) have emerged as a research hotspot in tumor treatment due to their advantages in spatiotemporal controllability. However, monomodal therapy suffers from inherent limitations. SDT is constrained by insufficient piezoelectric performance and the transient nature of ROS generation, while CDT is plagued by low catalytic efficiency, severely hindering clinical translation. To address these issues, this study constructs a polyethylene glycol-encapsulated iron-doped bismuth fluoride (BiF₃:Fe) nanosystem (BFFP) to achieve synergistic SDT-long-term CDT and induce cancer cell ferroptosis. Iron doping disrupts the central symmetry of the BiF₃ crystal lattice, inducing lattice distortion and enhancing piezoelectric performance. Under ultrasound irradiation, BFFP efficiently generates ^•OH and ^•O₂^- via the piezoelectric effect, enabling instantaneous ROS bursts for SDT. In the acidic tumor microenvironment, BFFP gradually degrades to expose active Fe²⁺/Fe³⁺ sites, which catalyze the sustained generation of ^•OH through Fenton-like reactions using endogenous H₂O₂, accomplishing long-term CDT. This instantaneous plus long-term ROS generation pattern synergistically depletes glutathione, inhibits glutathione peroxidase 4 activity, promotes accumulation of lipid peroxidation, and induces mitochondrial damage, ultimately triggering ferroptosis in tumor cells. This work provides a material paradigm and technical pathway for ROS-mediated long-term synergistic tumor therapy.