From Spark to Flame: ROS‐ and Light‐Cascade Activatable NIR‐II AIE Probe for Precise Tumor Imaging and Self‐Amplifying Phototherapy

Abstract The development of photoactivatable theranostic probes represents a major focus in precision tumor therapy. However, those previously reported probes often suffer from limited photoresponsivity, short excitation/emission wavelengths, and inactivity in the absence of light, restricting their ability to precisely diagnose deep‐seated tumors or enable effective phototherapy without auxiliary interventions. To address these challenges, this study designs a second near‐infrared (NIR‐II) aggregation‐induced emission (AIE) theranostic probe based on a dihydroindole skeleton, featuring dual reactive oxygen species (ROS)‐ and NIR light‐cascade activation. Upon ROS activation in the tumor microenvironment, TT‐DHIn undergoes transformation into TT‐In, exhibiting NIR‐II fluorescence emission and photodynamic/photothermal therapy (PDT/PTT) capabilities, thereby serving as a photoactivatable “guiding radar” with an exceptional signal‐to‐background ratio. Following pre‐activation, TT‐In efficiently generates ROS under 660 nm laser irradiation, enabling self‐supplementation of intratumor ROS. Furthermore, the intratumor TT‐DHIn undergoes cyclic conversion into TT‐In, significantly enhancing phototherapeutic efficacy and demonstrating potent in vitro cytotoxicity and in vivo tumor eradication. This dual‐activatable cascade strategy synergistically integrates tumor biomarker (ROS) responsiveness with photoactivation, offering a promising platform for NIR‐II imaging‐guided precision phototheranostics with strong potential for clinical translation.