Tumor‐Targeted Exosome‐Based Heavy Atom‐Free Nanosensitizers With Long‐Lived Excited States for Safe and Effective Sono‐Photodynamic Therapy of Solid Tumors

Theranostic nanosensitizers with combined near-infrared (NIR) fluorescence imaging and sono-photodynamic effects have great potential for use in the personalized treatment of deep-seated tumors. However, developing effective nanosensitizers for NIR fluorescence image-guided sono-photodynamic therapy remains a considerable challenge, including the low generation efficacy of reactive oxygen species (ROS), poor photostability, and the absence of cancer specificity. Herein, a novel heavy atom-free nanosensitizer is developed, which exhibits intense NIR fluorescence, high ROS generation efficiency, and improved aqueous stability. By conjugating a bulky and electron-rich group, 4-(1,2,2-triphenylvinyl)-1,1'-biphenyl (TPE), to the IR820 backbone, the resulting IR820 bearing TPE (IR820-TPE) effectively generates ROS via type I and II photochemical mechanisms under 808 nm laser irradiation. Moreover, TPE conjugation considerably increases the sono-photodynamic performance of IR820. To improve the intracellular delivery and tumor-targeting ability of IR820-TPE, biotin-conjugated exosome (B-Exo) is used as a natural nanocarrier. In vitro studies demonstrate the outstanding therapeutic performance of IR820-TPE-loaded B-Exo (IR820-TPE@B-Exo) in synergistic sono-photodynamic cancer therapy. In vivo studies reveal that IR820-TPE@B-Exo shows enhanced tumor accumulation, strong fluorescence signals, and effective sono-photodynamic therapeutic activity with high biosafety. This work demonstrates that IR820-TPE@B-Exo is a promising sono-phototheranostic agent for safe and targeted cancer therapy and NIR fluorescence imaging.