Achieving High‐Efficiency Type I Multimodal Photosensitizers via a Synergistic Rigidity‐Flexibility Strategy for Hypoxia‐Resistant Tumor Therapy

Phototheranostics, which integrates diagnosis and therapy through a single-molecule photosensitizer, has emerged as a promising approach for precision cancer treatment. Organic photosensitizers (PSs) are particularly noteworthy due to their adjustable structures, yet the development of effective multimodal PSs remains a significant challenge. This study innovatively proposes a molecular design strategy of "Donor-Acceptor (D-A) rigid coplanar skeleton grafting with flexible groups". Four D-A-type phenothiazine-based PSs were developed using dual donors of phenothiazine and triphenylamine, a tricyanofuran acceptor, and varied π-bridges. Among these, TPO2F exhibited a rigid planar structure through intramolecular hydrogen bonds, which led to enhanced molar extinction coefficients. Additionally, the introduction of flexible long alkyl chains into EL-TPO2F resulted in simultaneous improvements in near-infrared fluorescence brightness, type-I ROS generation, and photothermal efficiency. This synergistic improvement stems from the rigid skeleton ensuring efficient light harvesting, while flexible groups effectively suppress intermolecular π-π stacking. Experimental results demonstrated that EL-TPO2F NPs exhibit remarkable synergistic effects in photodynamic and photothermal therapy under both normoxic and hypoxic conditions. This study introduces a novel strategy for developing a highly efficient and hypoxia-resistant multimodal phototherapeutic nanoplatform, demonstrating significant potential for application in the treatment of hypoxic tumors.