A light-induced nitric oxide controllable release nano-platform based on diketopyrrolopyrrole derivatives for pH-responsive photodynamic/photothermal synergistic cancer therapy

Emerging treatment approaches, such as gas therapy (GT), photodynamic therapy (PDT) and photothermal therapy (PTT), have received widespread attention. The development of an intelligent multifunctional nano-platform responding to tumor microenvironments for multimodal therapy is highly desirable. Herein, a near-infrared (NIR) light-responsive nitric oxide (NO) photodonor (4-nitro-3-trifluoromethylaniline, NF) and a pH-sensitive group (dimethylaminophenyl) have been introduced into a diketopyrrolopyrrole core (denoted as DPP-NF). The DPP-NF nanoparticles (NPs) can be activated under weakly acidic conditions of lysosomes (pH 4.5-5.0) to generate reactive oxygen species (ROS) and enhance photothermal efficiency. The fluorescence detection demonstrated that NO controllable release can be realized by "on-off" switching of the NF unit under NIR light irradiation or dark conditions. The controllable NO release of DPP-NF NPs can not only trigger tumor cell death by DNA damage, but also overcome PDT inefficiencies caused by hypoxia in tumors. Additionally, DPP-NF NPs displayed 45.6% photothermal conversion efficiency, making them superior to other reported DPP derivatives. In vitro studies showed that DPP-NF NPs possessed low dark toxicity and high phototoxicity with a half-maximal inhibitory concentration of about 38 μg mL^-1. In vivo phototherapy indicated that DPP-NF NPs exhibited excellent tumor phototherapeutic efficacy with passive targeting of the tumor site via the enhanced permeability and retention (EPR) effect. These results highlight that the nano-platform has promising potential for NO-mediated multimodal synergistic phototherapy in clinical settings.