Protonic Acid/Viscosity-Activatable Type-I Photosensitizer via Donor and π-Bridge Modulation for Second Near-Infrared Imaging-Guided Photodynamic and Photothermal Therapy

Organic small molecules activated by the tumor microenvironment (TME) exhibit significant advantages over traditional organic small molecules in cancer diagnosis and therapy. This “on-demand activation” mode substantially reduces phototoxic damage to normal tissues. In this study, a protonic acid/viscosity-activatable Type-I theranostic probe TB-pH was rationally designed through a strategy of adjusting the donor unit and π-bridge structure. Owing to the lack of effective intramolecular charge transfer (ICT), TB-pH remains silent under normal physiological conditions. Upon specific activation by the protonic acid “key” in the TME, the molecule undergoes electronic rearrangement to form TB-H with a donor-π-acceptor (D-π-A) structure. The activated TB-H molecule exhibits excellent Type-I ( • OH) reactive oxygen species (ROS) generation, photothermal conversion, and NIR-II fluorescent emission capabilities under 808 nm laser irradiation. After cancer cell death induced by phototherapy, the increased intracellular viscosity in the tumor region leads to further enhancement of NIR-II emission of TB-H, providing an intuitive and effective method for real-time evaluation of tumor therapeutic efficacy. This study offers a new insight for developing protonic acid/viscosity-activatable specific photosensitizers with integrated NIR-II FL/PTT/PDT (Type-I) capabilities in the field of precise cancer therapy.