X-ray Induced Release of Nitric Oxide from Hafnium-Based Nanoradiosensitizers for Enhanced Radio-Immunotherapy.

Radiotherapy (RT) is an extensively used strategy for cancer treatment, but its therapeutic effect is usually limited by the abnormal tumor microenvironment (TME) and it lacks the ability to control tumor metastases. Herein, a nanoscale coordination polymer Hf-nIm@PEG (HNP) wa s prepared by the coordination of hafnium ions (Hf ) with 2-nitroimidazole (2-nIm), and then modified with lipid bilayers containing PEG. Under low-dose X-ray irradiation, on the one hand, Hf with high computed tomography signal enhancement ability can deposit radiation energy to induce DNA damage, and on the other hand, NO could be persistently released from 2-nIm, which could not only directly react with the radical DNA to prevent the repair of damaged DNA but also relieve the hypoxic immunosuppressive TME to sensitize radiotherapy. Additionally, NO can also react with superoxide ions to generate reactive nitrogen species (RNS) to induce cell apoptosis. More interestingly, w e discovered that Hf could effectively activate the cyclic-di-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to promote the immune responses induced by radiotherapy. Thus, ou r work presents a simple but multifunctional nanoscale coordination polymer to deposit radiation energy, trigger the release of NO, modulate the TME, activate the cGAS-STING pathway and finally realize synergistic radio-immunotherapy. This article is protected by copyright. All rights reserved.