A PDI-based NIR-II fluorescence imaging guided molecular phototheranostic platform for GSH-triggered gas therapy, mild photothermal therapy and NIR-activated photodynamic therapy

Synergistic therapy using multiple modalities is a highly promising therapeutic strategy. Near-infrared-II (NIR-II) fluorescence imaging, with its deep penetration and high fidelity, has frequently been employed in the literature to guide and assist treatment. Herein, we report the development of a NIR-II fluorescence imaging guided multi-therapy platform PDI-DS NPs, which integrates a novel activatable phototheranostic agent PDI-DBU, a H₂S donor DPS and an amphiphilic polymer DSPE-mPEG2000. In order to maximize redshift of absorption and emission of PDI derivatives, we introduced an electron donating group DBU on PDI to obtain PDI-DBU. PDI-DBU exhibits a distinct absorption band at 700–900 nm and demonstrates excellent NIR-II fluorescence emission/imaging properties and good photothermal effects under 808 nm laser irradiation. More importantly, under 808 nm laser irradiation, PDI-DBU could be oxidized, and the photodynamic effect of the material could be subsequently activated under 530 nm laser irradiation, achieving the combination of photothermal and activatable photodynamic dual modality treatment. The H₂S donor DPS, when triggered by the abundant glutathione (GSH) within the tumor microenvironment (TME), is capable of generating H₂S. On one hand, H₂S can inhibit tumor growth by disrupting mitochondrial function, on the other hand, it can also repress the expression of heat shock protein 90 (HSP90), thereby reversing tumor cell resistance mechanism against photothermal therapy. The utilization of PDI-DS NPs combined with DPS for efficient tumor ablation has been successfully demonstrated both in vitro and in vivo. This synergistic therapeutic platform thus offers a promising strategy in the field of NIR-II fluorescence imaging guided tumor therapy.