Neutrophil membrane-encapsulated nanosonosensitizer with ultrasound-reinforced ferroptosis in Pseudomonas aeruginosa pneumonia.

Pneumonia caused by Pseudomonas aeruginosa (P. aeruginosa) infection remains a formidable clinical challenge due to persistent biofilm formation and intrinsic antibiotic resistance, exacerbated by bacterial iron homeostasis that stabilizes biofilm architecture and neutralizes oxidative stress. Herein, we present Fe/TNT@NM, a biomimetic nanosonosensitizer activated by ultrasound (US) to dismantle biofilms through dual extracellular-intracellular mechanisms. The nanosonosensitizer features an iron-doped titanate nanotube (Fe/TNT) core encapsulated within a neutrophil membrane (NM). Under US irradiation, Fe/TNT@NM generates sonodynamic reactive oxygen species (ROS) extracellularly and enhances Fe release. These ions catalyze the Fenton reaction extracellularly to amplify chemodynamic effects and disrupt intracellular iron homeostasis, triggering bacterial ferroptosis. The NM coating enables immune evasion and biofilm-targeted delivery. This ultrasound-reinforced ferroptosis strategy synchronizes extracellular ROS storms with intracellular iron dyshomeostasis, achieving dual-action biofilm dismantling and eradication of drug-resistant P. aeruginosa. In a murine pneumonia model, Fe/TNT@NM suppresses biofilms and mitigates pulmonary injury. By converging biomimetic targeting, sonodynamic-chemodynamic cascades, and ultrasound-augmented ferroptosis, this nanosonosensitizer presents a paradigm-shifting approach to combat refractory biofilm infections and antibiotic resistance.