A Novel Activatable Nanoradiosensitizer for Second Near‐Infrared Fluorescence Imaging‐Guided Safe‐Dose Synergetic Chemo‐Radiotherapy of Rheumatoid Arthritis

Abstract The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo‐radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer‐40 (denoted as IRnR‐40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near‐infrared fluorescence (NIR‐II FL) imaging‐guided safe‐dose synergetic chemo‐radiotherapy. The high concentration of matrix metalloproteinase‐9 (MMP‐9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR‐40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real‐time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)‐mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR‐40 is believed to be the first attempt to achieve efficient NIR‐II FL imaging‐guided safe‐dose chemo‐radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.