Ultrasound-driven manganese oxide nanocatalyts augment multipronged catalytic tumor therapies by unleashing mutually enhanced and sustained oxidative strom and ferroptosis.

The catalytic strategies selectively eradicate tumors, but their efficacy is hindered by antioxidant defense mechanisms of tumor microenvironment (TME) and insufficient catalytic efficiency. Herein, we present a multifunctional manganese oxide nanosphere (MnOx NSs)-based antitumor platform that synergizes ultrasound (US)-triggered reactive oxygen species (ROS) generation with oxygen-independent sulfate radical (SO4•-) production to amplify oxidative damage. Under US irradiation, MnOx NSs generate hydroxyl radicals (•OH) and singlet oxygen (1O2) via sonodynamic effects, and Mn2+/Mn3+ species activate peroxymonosulfate (PMS) to produce SO4•- and •OH without oxygen reliance. Notably, US-induced electron-hole separation enables redox cycling between Mn3+/Mn4+ and Mn2+/Mn3+, creating a self-sustaining catalytic loop for continuous reactive species generation. Concurrently, enzyme-mimicking activities of MnOx NSs alleviating hypoxia and depleting glutathione in TME, thereby disrupting redox homeostasis. The TME remodeling, combined with oxidative storm induction, triggers ferroptosis which is driven by lipid peroxidation. In vitro and in vivo studies validate the efficacy and biosafety of this approach, demonstrating significant tumor suppression through synergistic oxidative storm and ferroptosis induction. This work highlights a paradigm-shifting strategy that integrates multi-catalytic reactivity, TME modulation, and regulated cell death pathways, offering a robust solution to overcome therapeutic barriers in antioxidant-rich tumors. The findings underscore the potential of manganese-based nanoplatforms in advancing next-generation catalytic oncology therapies.