Oxygen‐Enriched Metal‐Phenolic X‐Ray Nanoprocessor for Cancer Radio‐Radiodynamic Therapy in Combination with Checkpoint Blockade Immunotherapy

Abstract Radiotherapy (RT) based on DNA damage and reactive oxygen species (ROS) generation has been clinically validated in various types of cancer. However, high dose‐dependent induced toxicity to tissues, non‐selectivity, and radioresistance greatly limit the application of RT. Herein, an oxygen‐enriched X‐ray nanoprocessor Hb@Hf‐Ce6 nanoparticle is developed for improving the therapeutic effect of RT‐radiodynamic therapy (RDT), enhancing modulation of hypoxia tumor microenvironment (TME) and promoting antitumor immune response in combination with programmed cell death protein 1 (PD‐1) immune checkpoint blockade. All functional molecules are integrated into the nanoparticle based on metal‐phenolic coordination, wherein one high‐Z radiosensitizer (hafnium, Hf) coordinated with chlorin e6 (Ce6) modified polyphenols and a promising oxygen carrier (hemoglobin, Hb) is encapsulated for modulation of oxygen balance in the hypoxia TME. Specifically, under single X‐ray irradiation, radioluminescence excited by Hf can activate photosensitizer Ce6 for ROS generation by RDT. Therefore, this combinatory strategy induces comprehensive antitumor immune response for cancer eradication and metastasis inhibition. This work presents a multifunctional metal‐phenolic nanoplatform for efficient X‐ray mediated RT‐RDT in combination with immunotherapy and may provide a new therapeutic option for cancer treatment.