TiO2-Nanoparticle–Enhanced Sonodynamic Therapy for Prevention of Posterior Capsular Opacification and Ferroptosis Exploration of Its Mechanism

Purpose: To explore the application and potential ferroptosis mechanisms of sonodynamic therapy (SDT) using titanium dioxide nanoparticles (TiO2-NPs) as sonosensitizers for the prevention of posterior capsule opacification (PCO). Methods: We fabricated TiO2-NP-coated intraocular lenses (TiO2-IOLs) using the spin-coating method, followed by ultrasound activation of the photosensitizer TiO2. In vitro experiments were performed with human lens epithelial cells (HLECs) to explore the appropriate concentration of TiO2 and ultrasonic parameters. Investigations included reactive oxygen species (ROS) generation, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) western blot analysis, lipid peroxidation assays, and transcriptomics analysis. Finally, TiO2-IOLs were implanted in rabbit eyes to explore the in vivo performance of SDT. Results: Through both in vitro and in vivo experiments, the study determined that the ultrasound parameters of 5-minute duration, 1-MHz frequency, 50% duty cycle, and 1.2-W/cm2 intensity were reliable and valid for killing HLECs without damaging other ocular structures. In vitro experiments demonstrated that SDT generated excess ROS, which disrupted the mitochondrial membrane potential and significantly reduced the GSH content. Additionally, the downregulation of GPX4, accumulation of lipid peroxides, and alteration of mitochondrial morphology were observed, suggesting that ferroptosis may be the underlying mechanism. The RNA-sequencing analysis results also showed an increase in the expression of multiple pro-ferroptosis genes and the ferroptosis marker gene PTGS2. Animal experiments preliminarily demonstrated the safety and effectiveness of SDT in treating PCO in vivo. Conclusions: TiO2-IOLs combined with SDT effectively prevented PCO by generating ROS and intracellular ferroptosis.