Ultrasound-Propelled ferroptosis catalytic amplification for Active-targeting sonodynamic anti-tumor therapy with Concurrent Photoacoustic/MRI visualization.

Sonodynamic therapy (SDT) faces significant challenges in treating aggressive malignancies due to inherent apoptotic resistance. To address this, we developed a multifunctional nanoliposome designed for mitochondrial targeting and synergistic induction of dual cell death pathways. Co-loaded with the sonosensitizer HMME and an iron-based Fenton catalyst, the nanoparticle exhibits glutathione-responsive disassembly and promotes robust reactive oxygen species generation under ultrasound irradiation. This leads to potent lipid peroxidation and ferroptosis, effectively bypassing conventional resistance mechanisms. The platform further integrates dual-modal magnetic resonance and photoacoustic imaging capabilities, enabling precise tumor delineation and real-time treatment monitoring. Constructed entirely from clinically approved lipid components, our nanoplatform demonstrates excellent biocompatibility and achieves complete tumor regression in murine models without significant systemic toxicity. This work provides a comprehensive theranostic strategy that combines catalytic amplification with multimodal imaging, offering a clinically translatable approach for the precision treatment of therapy-resistant malignancies.