Ultrasound-activated hollow FeOOH/MnO2 nanocatalysts for tumor barrier disruption and synergistic sonodynamic-ferroptosis therapy

Breast cancer treatment is often hindered by dense tumor stromal and extracellular matrix barriers, which limit the efficacy of conventional therapies. Sonodynamic therapy (SDT) has emerged as a promising noninvasive strategy to overcome these barriers, while its efficacy is often limited by insufficient reactive oxygen species (ROS) generation. Here, a rationally designed sonocatalytic nanoplatform composed of hollow FeOOH-modified MnO 2 nanoparticles (HFM) was synthesized for the SDT of breast cancer. First, FeOOH modification and ate the electronic band structure of HFM, producing a more negative conduction band that facilitates ultrasound (US)-triggered electron transfer and boosts ROS production. Additionally, the Mn component enables sonocatalytic glutathione (GSH) depletion, which, when combined with Fe-mediated iron overload, amplifies oxidative stress and triggers ferroptosis. Simultaneously, US-induced cavitation transiently disrupts tumor interstitial and extracellular matrix barriers, enhancing deep intratumoral penetration of HFM and further potentiating its therapeutic efficacy. In vitro and in vivo studies demonstrate that US-activated HFM induces ferroptosis-related gene regulation, deep tumor penetration, and robust antitumor efficacy with minimal systemic toxicity. Collectively, this work presents a multifunctional sonosensitizer with enhanced catalytic activity, barrier-penetrating capability, and ferroptosis-inducing potential, offering a promising strategy for US-augmented breast cancer therapy.