Wool Keratin-Engineered Manganese Nanozyme with Tumor Microenvironment-Adaptive Self-Cascade Capability for...

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, poses a substantial global health challenge with high mortality and poor therapeutic outcomes, especially in advanced stages. Current therapeutic approaches for HCC, including surgical resection, targeted therapy, immunotherapy, and radiotherapy, are often limited by drug resistance, systemic toxicity, and the complex tumor microenvironment (TME). Herein, we establish the first wool keratin-guided Mn₃O₄ nanozymes (MnWK) with self-cascade catalytic capability that systematically transforms the TME into a pro-oxidative microenvironment, achieving high therapeutic efficacy through synergistic hypoxia alleviation and ROS-mediated apoptosis. The introduction of WK not only enhances the biocompatibility and colloidal stability of Mn₃O₄ nanoparticles, but also improves their catalytic performance to enable efficient cascade reactions under physiological conditions. Within the mildly acidic and H₂O₂-rich TME, MnWK exhibits dual catalase (CAT) and oxidase (OXD)-mimicking activities, driving a well-defined two-step catalytic cascade. Specifically, it first decomposes endogenous H₂O₂ into O₂ to effectively alleviate tumor hypoxia, then converts the in situ generated O₂ into cytotoxic superoxide anions. This cascade amplifies oxidative stress and induces selective cancer cell apoptosis via the p38/JNK MAPK signaling pathway. Overall, this work establishes a promising TME-adaptive self-cascade nanotherapeutic system for advancing HCC management.