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.