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

Abstract 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.