Unveiling the active sites on ferrihydrite with apparent catalase-like activity for potentiating radiotherapy

The use of catalase-like nanozymes in relieving tumor hypoxia has been a promising strategy for adjuvant radiotherapy, yet their catalytic mechanism and toxic potential remain elusive. While most studies on catalase-like mechanisms focus on the substrates and products in the catalytic process, little is reported to analyze the dominating surface structure for catalytic activity of nanozymes. Here, we reported the catalase-like activity of ferrihydrite and revealed its structure-activity relationship. Among the ten main forms of iron oxide nanomaterials, ferrihydrite, especially 2-line ferrihydrite, exhibited the highest catalase-like activity. Importantly, the structure-activity fitting and density functional analysis revealed that the abundant surface iron-associated hydroxyl groups dominantly affect the catalase-like activity of ferrihydrites. In addition, the ferrihydrite exhibited no peroxidase-like and superoxide dismutase-like activities, and constantly catalyzed the decomposition of H2O2 to release O2 in the pH range of 4.0–8.7. With the help of steady and single catalase-like activity in the physiological environment, ferrihydrite safely and effectively catalyzed the H2O2 in tumor microenvironment to in-situ produce O2 and significantly enhanced the therapeutic effect of radiotherapy. Moreover, ferrihydrite exhibited excellent biosafety and biodegradability. These findings demonstrate the great potential of ferrihydrite as a biocompatible catalase-like nanozyme for relieving hypoxia in cancer therapy.