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.