Radiation-activated PD-L1 Aptamer-Functionalized Nanoradiosensitizer to Potentiate Antitumor Immunity in Combined Radioimmunotherapy and Photothermal Therapy

Reactive oxygen species (ROS)-mediated immunogenic cell death (ICD) is crucial in radioimmunotherapy by boosting innate antitumor immunity. However, the hypoxic tumor microenvironment (TME) often impedes ROS production, limiting the efficacy of radiotherapy. To tackle this challenge, a combination therapy involving radiotherapy and immune checkpoint blockade (ICB) with anti-programmed death-ligand 1 (PD-L1) has been explored to enhance antitumor effects and reprogram the immunosuppressive TME. Here, we introduce a novel PD-L1 aptamer-functionalized nanoradiosensitizer designed to augment radiotherapy by increasing X-ray deposition specifically at the tumor site. This innovative X-ray-activated nanoradiosensitizer, comprising gold-MnO2 nanoflowers, efficiently enhances ROS generation under single low-dose radiation and repolarizes M2-like macrophages, thereby boosting antitumor immunity. Additionally, the ICB inhibitor BMS-202 synergizes with the PD-L1 aptamer-assisted nanoradiosensitizer to block the PD-L1 receptor, promoting T cell activation. Furthermore, this nanoradiosensitizer exhibits exceptional photothermal conversion efficiency, amplifying the ICD effect. The PD-L1-targeted nanoradiosensitizer effectively inhibits primary tumor growth and eliminates distant tumors, underscoring the potential of this strategy in optimizing both radioimmunotherapy and photothermal therapy.