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

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.