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

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 H2O2 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.