A Self‐Catalytic NO/O₂ Gas‐Releasing Nanozyme for Radiotherapy Sensitization through Vascular Normalization and Hypoxia Relief

Abstract Radiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor‐targeted “prosthetic‐Arginine” coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O₂) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO‐donating Fmoc‐protected Arginine and Ru³⁺ ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu‐HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O₂ and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O₂ levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O₂‐transporting ability of heme, HRRu‐HFn nanozymes also deliver O₂ directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O₂ production, alongside targeted delivery, enable the HRRu‐HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu‐HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.