Near‐Infrared II Light‐Triggered Robust Carbon Radical Generation for Combined Photothermal and Thermodynamic Therapy of Hypoxic Tumors

Abstract Tumor hypoxia is a major cause of failure in cancer therapy, and there is almost no efficacious treatment for hypoxic tumors. Herein, an azo‐containing polymer (P2) is designed to encapsulate IR1061, and further covalently grafted with a tumor‐targeting tripeptide RGD to form P2@IR1061‐RGD NPs for combined photothermal and thermodynamic therapy (PTT/TDT) in the near‐infrared II (NIR II) biowindow (1000–1700 nm). Upon 1064 nm laser irradiation, IR1061 generates heat to break the azo bonds of P2, achieving robust carbon radical generation, which induces cancer cell death even under a hypoxic tumor microenvironment. RNA‐sequencing is first adopted to unveil the impact of combined PTT/TDT on the cell transcriptome and the corresponding pathways using 4T1 breast cancer cells. The dysregulated genes are involved in protein processing within the endoplasmic reticulum, cell cycle regulation, ubiquitin‐mediated proteolysis, and DNA replication pathways. The tumor inhibition rates on a 4T1 breast cancer model as well as on a patient‐derived xenograft model of hepatocellular carcinoma (PDX HCC ) are 97% and 100%, and negligible systematic toxicity is observed. This study proposes the application of an azo‐containing polymer for safe and efficient combined PTT/TDT in the NIR II biowindow, as a promising strategy for clinical treatment of hypoxic tumors.