Personalized Carbon Monoxide‐Loaded Biomimetic Single‐Atom Nanozyme for Ferroptosis‐Enhanced FLASH Radioimmunotherapy

Abstract Ultra‐high dose rate radiotherapy (FLASH‐RT) has emerged as a novel tool for cancer radiotherapy owing to its extremely rapid radiation delivery to target species. Although FLASH‐RT can protect normal tissues and organs, tumor self‐protection mechanisms limit its therapeutic effect, thus necessitating technological improvement. Here, a multipathway ferroptosis‐enhanced radioimmunotherapeutic strategy that combines single‐atom nanozyme (SAzyme)‐based GSH depletion and CO gas therapy is reported. Personalized FLASH radioimmunotherapy is achieved through encapsulation of the carbon monoxide donor (MnCO)‐loaded porous Pd‐C SAzyme (SM) within 4T1 cancer cell membranes (CSM). Camouflaging with the cancer cell membrane enables the navigation of the MnCO‐loaded Pd‐C SAzyme to the tumor region via homologous targeting. There, it releases MnCO, which generates CO from overexpressed H 2 O 2 to induce mitochondrial apoptosis. Furthermore, the generated CO and Pd‐C SAzyme oxidized glutathione and downregulates glutathione peroxidase 4 (GPX4) expression to induce ferroptosis. The palladium in the SAzyme of the CSM further enhances the photoelectric effects of FLASH‐RT. The CSM‐mediated FLASH‐RT also invokes potent antitumor immunity, suppressing distant tumors, and immune memory, inhibiting tumor recurrence. This work presents a unique personalized nanozyme and CO gas synergistic approach wherein FLASH radioimmunotherapy avoids damage of normal tissues while simultaneously inducing ferroptosis for orthotopic tumor treatment.