Genistein and chlorin E6-loaded versatile nanoformulation for remodeling the hypoxia-related tumor microenvironment and boosting photodynamic therapy in nasopharyngeal carcinoma treatment

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a poor prognosis that is usually advanced at the time of diagnosis. Photodynamic therapy (PDT), with its safety and reproducibility, offers significant potential for advanced NPC treatment, though its efficacy is hindered by the hypoxic tumor microenvironment and continuous oxygen depletion during therapy. This study presents a versatile nanoformulation (CGP) co-loaded with chlorin e6 (Ce6) and genistein (Gen) within peptide dendritic nanogel (PDN) for enhanced NPC treatment. The positively charged CGP is efficiently internalized by NPC cells, followed by glutathione (GSH)-responsive degradation, releasing Ce6 and Gen. The released Gen reduces intracellular oxygen consumption and tumor metastability by inhibiting the HIF-1 signaling pathway, thereby efficiently boosting PDT efficacy. In vitro and in vivo studies confirmed that the combination of Gen and PDT effectively eliminates tumors and inhibits metastasis. Multi-omics analysis (RNA sequencing and targeted energy metabolomics) revealed that CGP suppresses HIF-1 alpha, GLUT1, and VEGFA expression, downregulating the HIF-1 pathway and reducing anaerobic glycolysis, thereby successfully remodeling the hypoxia-associated tumor microenvironment. This study demonstrates that the Gen-PDT combination is a versatile approach capable of enhancing PDT efficacy and holds promise for NPC management.