Abstract

Docetaxel (DTX)-based concurrent chemoradiotherapy (CCRT) is an important treatment for locally advanced non-small cell lung cancer (NSCLC), but its efficacy is limited by systemic toxicity and radioresistance. Here, we propose an oxidative priming strategy using plumbagin (PLB), a natural redox modulator, to disrupt tumor redox homeostasis and enhance DTX-mediated chemoradiotherapy. PLB markedly sensitized NSCLC cells to DTX, reducing the effective DTX concentration by 33.3-fold in LLC cells and 18-fold in A549 cells. To overcome the pharmacokinetic mismatch between DTX and PLB, we developed a folate receptor-targeted PEGylated liposomal nanoformulation for synchronized co-delivery. This formulation amplified intracellular ROS accumulation to approximately 2.5 times that induced by X-ray alone and 3.3 times that induced by (DTX + PLB)-NP alone, thereby enhancing radiation-induced DNA damage and apoptosis. In vivo, X-ray combined with the targeted nanoformulation achieved a tumor inhibition rate of 99%, while maintaining stable body weight and showing no obvious hematological, hepatic, or renal toxicity. This study provides a redox-guided nanomedicine strategy to enhance DTX-based CCRT for NSCLC at low doses while maintaining favorable preliminary biosafety.