Molecular Engineering of Biomarker-Activatable Type I NIR Photosensitizer Enables Precision-Guided Photodynamic...

Photodynamic therapy (PDT) faces significant challenges in treating solid tumors due to the hypoxic tumor microenvironment and high degree of tumor heterogeneity. To address this issue, this study employed a strategy of acceptor planarization coupled with tunable terminal aryl modulation to design and synthesize a series of type I photosensitizers (DPP-1-DPP-3) with systematically tuned push-pull character and electronic structures. Among them, DPP-3 exhibits outstanding near-infrared emission and hypoxia-tolerant reactive oxygen species generation. Building on this core module, we integrated a biomarker-responsive unit into DPP-3 to construct an intelligent theranostic probe, DPP-CE. This probe retains high photodynamic activity both before and after activation, ensuring reliable therapeutic efficacy independent of local activation efficiency, while its near-infrared fluorescence signal is specifically activated only within the tumor microenvironment, enabling imaging-guided precise treatment. Both in vitro and in vivo experiments demonstrate that DPP-CE allows high-contrast fluorescence imaging of tumors and effectively inhibits tumor growth under both normoxic and hypoxic conditions, while showing good biosafety. This work not only provides a new strategy for developing high-performance type I photosensitizers, but also offers a modular approach that integrates a therapeutic core with a biomarker-responsive unit, paving the way toward programmable theranostic platforms adaptable to tumor heterogeneity.