Sonocatalytic Eradication of Hepatocellular Carcinoma by Tailoring Structural Defects of Black Indium Oxide Sonocatalysts and Leveraging Apoptosis/Ferroptosis‐Hybridized Pathways

ABSTRACT Hepatocellular carcinoma, a malignant tumor with high incidence and mortality rates, urgently requires the development of novel therapeutic strategies that are highly efficient and minimally toxic. Sonodynamic therapy has garnered significant attention due to its non‐invasiveness, deep tissue penetration capability, and low side effects, yet its efficacy is highly dependent on the development of high‐performance sonocatalyst. This study successfully prepared Pd‐integrated indium oxide with abundant structural defects as a novel sonocatalyst for the highly efficient sonocatalytic eradication of hepatocellular carcinoma. Furthermore, Pd confers catalase‐like and peroxidase‐like enzymatic activities, modulating the tumor microenvironment to alleviate hypoxia and augment hydroxyl radical production, consequently amplifying sonocatalytic efficacy. Mechanistic insights identify a synergistic pathway involving both apoptosis and ferroptosis. This hybridized apoptotic/ferroptotic pathway acts synergistically to amplify oxidative cellular damage, ultimately achieving significant suppression and eradication of hepatocellular carcinoma. This work not only provides a novel strategy for designing efficient sonosensitizers through defect engineering but also unveils a new mechanism whereby engineered sonocatalysts can treat cancer by triggering hybridized cell death pathways, offering a promising approach and theoretical foundation for the sonodynamic therapy of liver cancer.