M1-Polarized Macrophage Exosome Biomimetic Nanozyme Bioreactor for Nanozyme-Based Catalytic Tumor Therapy

Nanozyme-based catalytic therapy holds great promise for tumor treatment, but its clinical translation is often hampered by limited biocompatibility, poor targeting efficiency, and diminished catalytic performance under hypoxic conditions. In this study, we designed a multifunctional biomimetic nanozyme bioreactor (MEFR) by coassembling Fe₃S₄ nanozymes, M1-derived macrophage-derived exosomes (M1 Exos), and the hemoglobin allosteric effector RSR13. The MEFR exhibits strong peroxidase-like activity, efficiently catalyzing the conversion of endogenous H₂O₂ into cytotoxic hydroxyl radicals (·OH) for effective tumor cell elimination. The inclusion of RSR13 relieves tumor hypoxia, thereby enhancing the oxygen-dependent catalytic activity of the MEFR. Moreover, M1 Exos confer homotypic targeting and immunomodulatory effects by promoting the repolarization of tumor-associated macrophages from the M2 phenotype to the M1 phenotype. The MEFR exhibits efficient tumor accumulation, deep intratumoral penetration, and potent antitumor efficacy both in vitro and in vivo, with negligible systemic toxicity. This study presents a novel strategy for the construction of intelligent nanozyme platforms enabling precise and effective catalytic tumor therapy.