High-efficiency phototheranostics with ultrahigh extinction coefficient via weak donor engineering for near-infrared IIb fluorescence imaging guided type-I/II photodynamic/photothermal combination therapy

The development of small molecule-based nanoagents that simultaneously possess an ultrahigh extinction coefficient, bright near-infrared IIb (NIR-IIb, 1500-1700 nm) fluorescence emission, efficient reactive oxygen species (ROS) generation in hypoxic microenvironments, and excellent photothermal performance is of considerable importance for high-efficiency phototheranostics, yet it remains difficult to realize in a single system. Herein, a tactic centering on "regulating the electron-donating ability of the weak donor (D) unit" is applied for the construction of small molecules with enhanced light-harvesting capability, thereby optimizing fluorescence emission and photodynamic/photothermal performances. As a proof-of-concept, by coupling the strong acceptor (A) and D' moieties with different weak D moieties, three A-D'-D-D'-A type molecules (DP2F, DPOF, and DP2O) are designed. Compared to DP2F and DPOF, the maximum absorption wavelength of DP2O exhibited an obvious redshift due to the enhanced electron-donating ability of the D unit. Notably, the corresponding DP2O nanoparticles (NPs) possess an ultrahigh extinction coefficient (ε) of (2.6 ± 0.1) × 10⁵ M^-1 cm^-1 at 831 nm. To the best of our knowledge, this value of ε is considerably higher than those of most reported organic nanomaterials. Consequently, the DP2O NPs exhibited strong NIR-IIb fluorescence emission, enabling high-resolution in vivo imaging of the whole vessel network and tumors. Moreover, the DP2O NPs displayed satisfactory type-I/II ROS generation and hyperthermia induction, leading to efficient inhibition of tumor growth in vivo.