GLUT-Mediated Uptake of Glyco-Trojan Horse Enables Targeted PDT for Breast Cancer.
Porphyrin photosensitizers for photodynamic therapy (PDT) are often limited by poor solubility, aggregation, and insufficient tumor selectivity. Here, fructose-decorated porphyrin core-cross-linked star glycopolymers (CGs) were constructed via an arm-first ATRP strategy, affording a covalently stabilized porphyrin core and a fructose-rich corona. After deprotection, the CGs were readily dispersible in water and retained characteristic photophysical properties with efficient singlet oxygen generation. The optimized formulation, C5G, showed higher uptake in MCF-7 cells than in HepG2 cells, and this uptake was reduced by fructose-containing competitors and a broad GLUT inhibitor. Under light irradiation, C5G induced strong intracellular ROS production and pronounced apoptosis-dominated phototoxicity with negligible dark toxicity. Transcriptomic analysis revealed coordinated regulation of stress-response and cell-death associated pathways following PDT. These results demonstrate that fructose-functionalized core-cross-linked star glycopolymers enable GLUT-mediated targeted PDT and provide a stable and selective nanoplatform for breast cancer therapy.