The enhanced photothermal therapy against gastric cancer by mitochondria/STAT3-targeted nanoplatform with OXPHOS blocking

Near-infrared (NIR) photothermal therapy (PTT) has provided an innovative modality for the ablation of gastric cancer (GC) with minimized damage to normal tissues. However, the upregulation of heat shock proteins (HSPs) and the abnormal vascularization at the tumor site, as well as the low specificity with the diffusional hindrance of therapeutic agents to cancer cells, severely hamper this mono-therapeutic strategy. To overcome these obstacles, we designed and prepared a mitochondria/STAT3-targeted nanoplatform (ATO/CR NPs), which is self-assembled by Drug Administration (FDA)-approved atorvaquinone (ATO) and NIR phototherapeutic agent CR to fight GC. The ATO/CR NPs exhibit enhanced PTT efficiency owing to the oxidative phosphorylation (OXPHOS) blocking in mitochondria for the downregulation of ATP and HSP based on ATO. More importantly, the ATO from ATO/CR NPs can also specifically target STAT3 in GC cells to restrain proliferation, inhibit angiogenesis, and promote apoptosis. Hence, the multimodal NIR ATO/CR NPs initiate accurate targeting of cancer cells, triggering serious mitochondrial dysfunction and cellular apoptosis to amplify the photo-ablation activity, which provides a promising strategy for GC treatment, warranting further preclinical exploration. The mitochondria/STAT3-targeted ATO/CR NPs can specifically accumulate in tumor tissue through the EPR effect and active targeting STAT3 protein in gastric cancer cells, which will boost apoptosis, suppress proliferation, restrain angiogenesis activity, and block OXPHOS to decrease the ATP generation with HSPs inhibition for PTT promotion, providing a promising avenue in gastric cancer therapy for further preclinical investigation. • A superior therapeutic agent (ATO/CR NPs) can initiate precise targeting in gastric cancer (GC), triggering serious mitochondrial dysfunction and cellular apoptosis. • The atovaquone from ATO/CR NPs not only can block OXPHOS to decrease the ATP generation with HSPs inhibition but also can target STAT3 to limit anti-apoptotic Bcl-2 level, and restrain the angiogenesis activity, as well as impede cell cycle-related proteins (Cyclin D1, CDK4, CDK6), inducing promoted GC photo-ablation activity. • In vitro and in vivo experiments prove that the ATO/CR NPs present superb biocompatibility, slight dark toxicity, strong phototoxicity, and desired tumor ablation properties.