Cobalt Single‐Atom Nanozyme for Enhanced Intestinal Radioprotection and Tumor Radiosensitization via Bidirectional ROS Modulation

ABSTRACT Herein, we develop an orally administered cobalt single‐atom nanozyme (Co‐SAN) featuring pH‐responsive, bifunctional catalytic activity to enable simultaneous intestinal radioprotection and tumor radiosensitization. In the alkaline intestinal microenvironment, Co‐SAN effectively scavenges radiation‐induced reactive oxygen species (ROS)‐as validated by flow cytometry, thereby mitigating radiation‐induced intestinal injury (RIII). Mechanistically, RNA‐seq analysis reveals that beyond direct ROS elimination, Co‐SAN downregulates the ROS‐mediated PI3K/AKT signaling pathway, significantly suppressing the formation of detrimental neutrophil extracellular traps (NETs). Furthermore, this highly biocompatible nanozyme maintains gut microbiota homeostasis and preserves intestinal barrier integrity. In contrast, within the mildly acidic tumor microenvironment (TME), Co‐SAN undergoes a catalytic switch to promote ROS generation and ameliorate hypoxia, potently augmenting radiotherapeutic efficacy. Collectively, this study presents a bifunctional single‐atom nanozyme that resolves the spatial contradiction between normal tissue protection and targeted tumor sensitization, offering a promising paradigm to substantially widen the therapeutic window of radiotherapy.