pH-Activatable Long-Wavelength Photosensitizers for Thermal-Free Traceable Photodynamic Therapy

Critical limitations in current clinical photodynamic therapy (PDT) include shallow tissue penetration, systemic phototoxicity, and low singlet oxygen yield (Φ 1 O 2 ) of photosensitizers (PSs). Tumor-specific activatable near-infrared (NIR) PSs are hopeful to overcome the limitations of traditional PDT. However, their low Φ 1 O 2 usually requires high power density laser irradiation employed in long-wavelength PDT to produce thermal energy and then to synergistically enhance PDT. The strong photothermal radiation caused acute pain significantly reduces the patient compliance and hinders the broader clinical application of long-wavelength PDT. Our work addresses these challenges comprehensively by designing a series of pH-activatable cyanine/hemicyanine-based PSs with high Φ 1 O 2 , which enables activatable fluorescence and/or photoacoustic imaging-escorted efficient PDT without the synergy of photothermal energy, sparking further research into innovative approaches to enhance the efficacy and tolerability of PDT.