Immunotherapy for colorectal cancer (CRC) is still clinically limited by the extremely immunosuppressive tumor microenvironment. Fusobacterium nucleatum (Fn) selectively colonizes CRC tumors and drives immunosuppression by persisting in macrophages and driving their M2 polarization. We designed a self-activating polymer nanozyme composed of iron-containing xanthan polymer and artemisinic acid (AS) as the payload, which is used to eliminate the Fn storage pool within macrophages and reprogram the macrophage immune ecosystem. These nanozymes are specifically engulfed by M2-like Fn-infected macrophages through mannose receptor-mediated endocytosis, and then are activated intracellularly by overexpressed hydrogen activation, releasing ferrous ions and AS, which synergistically amplify the generation of cytotoxic reactive oxygen species (ROS) through Fenton chemistry. At the same time, AS induces autophagy in macrophages, promoting the co-localization of the nanozyme-bacteria in autophagosomes, to enhance Fn killing mediated by ROS. It is noteworthy that the elimination of intracellular Fn not only reverses the immunosuppressive phenotype of infected macrophages but also triggers paracrine signaling, driving the M1 re-polarization of adjacent uninfected macrophages. In xenograft and orthotopic CRC models containing intracellular Fn, the nanozyme can efficiently eliminate intracellular Fn and systematically reshape the macrophage immune architecture, significantly enhancing the therapeutic effect of anti-CD47 immunotherapy. This study proposes a strategy to improve CRC immunotherapy by precisely targeting bacteria within tumor-associated macrophages. This study was published in ACS Nano under the title "Engineered Self-Activatable Polymeric Nanozymes Precisely Eradicate Tumor-Associated Intramacrophage Bacteria to Potentiate Immunotherapy Based on Cluster of Differentiation 47 Blockade".
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DOI: 10.1021/acsnano.5c15423