Nitric Oxide-Releasing Nanoscale Metal-Organic Layer Overcomes Hypoxia and Reactive Oxygen Species Diffusion Barriers to Enhance Cancer Radiotherapy

Hafnium (Hf)-based nanoscale metal-organic layers (MOLs) enhance radiotherapeutic effects of tissue-penetrating X-rays via a unique radiotherapy-radiodynamic therapy (RT-RDT) process through efficient generation of hydroxy radical (RT) and singlet oxygen (RDT). However, their radiotherapeutic efficacy is limited by hypoxia in deep-seated tumors and short half-lives of reactive oxygen species (ROS). Herein the conjugation of a nitric oxide (NO) donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), to the Hf₁₂ secondary building units (SBUs) of Hf-5,5′-di-p-benzoatoporphyrin MOL is reported to afford SNAP/MOL for enhanced cancer radiotherapy. Under X-ray irradiation, SNAP/MOL efficiently generates superoxide anion (O₂^−.) and releases nitric oxide (NO) in a spatio-temporally synchronized fashion. The released NO rapidly reacts with O₂^−. to form long-lived and highly cytotoxic peroxynitrite which diffuses freely to the cell nucleus and efficiently causes DNA double-strand breaks. Meanwhile, the sustained release of NO from SNAP/MOL in the tumor microenvironment relieves tumor hypoxia to reduce radioresistance of tumor cells. Consequently, SNAP/MOL plus low-dose X-ray irradiation efficiently inhibits tumor growth and reduces metastasis in colorectal and triple-negative breast cancer models.