Ultrasound-accelerated Ti3FeBi5O15 nanosheets amplify reactive oxygen species storms/ferroptosis to trigger antitumor immunotherapy

Abstract

Insufficient intracellular Fe²⁺ ions availability and hypoxic tumor microenvironment significantly hamper the efficiency of ferroptosis. There is an urgent need for breakthrough research in the development and delivery of ferroptosis inducers and the reprogramming of the immune microenvironment. Herein, Ti₃FeBi₅O₁₅ (TFBO) piezoelectric nanosheets were engineered to amplify ferroptosis and trigger immunogenic cell death via ultrasound (US) activation. TFBO nanosheets feature a narrow bandgap (2.03 eV) and high piezoelectric coefficient (d₃₃ = 22.1 pm V⁻¹), enabling efficient electron-hole separation under US irradiation. Notably, TFBO nanosheets generate an internal piezoelectric field that promotes Fe³⁺ to Fe²⁺ conversion and ·OH generation from H₂O under US irradiation, while simultaneously depleting intracellular GSH under US irradiation, leading to lipid peroxidation and GPX4 suppression. Importantly, TFBO nanosheets activate immunogenic cell death (ICD), stimulating antitumor immune responses. Therefore, combined with its high biocompatibility, effective tumor inhibiting performance, and minimal systemic toxicity, TFBO represents a mechanistically distinct and translationally promising ferroptosis amplifier for tumor therapy.