Nitroreductase-Responsive Fluorescent “Off-On” Photosensitizer for Hypoxic Tumor Imaging and Dual-Modal Therapy

Photothermal therapy synergized with photodynamic therapy for the treatment of tumors has emerged as a promising strategy. However, designing photosensitizers with both high photothermal efficiency and high photodynamic performance remains challenging. In contrast, the strategy of rationalizing the design of photosensitizers using the physiological properties of tumors to improve the photon utilization of photosensitizers during phototherapy is more advantageous than the approach of endowing a single photosensitizer with complex functions. Herein, we propose a molecular design (CyNP) to convert from photothermal therapy to photodynamic synergistic photothermal therapy based on the prevalent properties of hypoxic tumors. In the normoxic region of tumors, the deactivation pathway of CyNP excited state is mainly the conversion of photon energy to thermal energy; in the hypoxic region of tumors, CyNP is reduced to CyNH by nitroreductase, and the deactivation pathway mainly includes radiation leap, energy transfer between CyNP and oxygen, and conversion of photons energy to heat energy. This strategy enables real-time fluorescence detection of hypoxic tumors, and it also provides dual-mode treatment for photothermal and photodynamic therapy of tumors, achieving good therapeutic effects in vivo tumor treatment. Our study achieves more efficient tumor photoablation and provides a reference for the design ideas of smart photosensitizers.