Sono-tribocatalytic therapy provokes PANoptosis in cancer cells.

The rapid progress of interdisciplinary medicine has significantly boosted ultrasound-based therapeutic modalities and strategies. The sonosensitizers, as core components of traditional sonodynamic therapy, have drawn escalating research focus for their unique therapeutic performance, but their clinical translation remains severely hampered by critical bottlenecks of biodegradability, required semiconductor characteristic, and long-term biosafety risks, which underscore an urgent demand for innovative sonosensitizers coupled with breakthrough therapeutic modalities to revolutionize ultrasound-based therapeutics. Herein, we strategically engineered the optimized iron oxyhydroxide nanorods as a high-performance ultrasound-activated sono-tribocatalytic nanosystem for efficient sono-tribocatalytic therapy (STT). This sono-tribocatalytic sonosensitizer demonstrates exceptional tribocatalytic efficacy in radical generation while maintaining excellent recyclability. Its mechanism originates from the surface charges on sonosensitizers generated by tribocatalysis that interact with dissolved oxygen and hydroxyl species, which generate reactive oxygen species to drive redox reactions. Crucially, the accumulated cytotoxic hydroxyl and superoxide radicals induce simultaneous mitochondrial dysfunction and redox homeostasis disruption in cancer cells, triggering specific PANoptosis. The in vivo assessments validate its potent antineoplastic effect. It achieves remarkable tumor inhibition through mechano-chemical activation by the intrinsic STT mechanism. This study establishes the first STT paradigm capable of inducing PANoptosis for efficient cancer treatment, thereby significantly expanding the application scope of sonocatalytic medicine to diverse disease interventions.