Nitric Oxide-Releasing Molecular Co-Assembly Enables Epithelial-Mesenchymal Transition Suppression and Intermolecular Electron Transfer-Enhanced Type-I Photodynamic Therapy.

Abstract

Epithelial-mesenchymal transition (EMT) mediated metastasis remains the primary contributor to cancer-related mortalities worldwide, highlighting the critical need for therapeutic strategies that simultaneously eradicate primary tumors and suppress metastatic progression. However, conventional photodynamic therapy (PDT), particularly oxygen-dependent type-II photosensitizers, suffers from hypoxia-limited efficacy and may even induce EMT under suboptimal treatment conditions. Herein, we report enhanced type-I reactive oxygen species (ROS)-generating nanoparticles (NPs) based on the coassembly of two structurally similar small molecules (TQTT-NO and TQTT-NH), integrating light-controlled nitric oxide (NO) release to synergistically inhibit tumor growth and EMT. By leveraging precise molecular structure matching, the coassembled NPs (TQTT-NO/NH NPs) enable efficient intermolecular electron transfer, as revealed by the photocurrent results and Gibbs free energy calculations, thereby favoring type-I ROS generation under white-light irradiation while simultaneously triggering on-demand NO release. The developed TQTT-NO/NH NPs effectively suppress transforming growth factor-β (TGF-β)-induced EMT, inhibit cancer cell migration and invasion in vitro, and markedly reduce primary tumor growth and lung metastasis in a murine tumor model under light activation. Overall, this work establishes a generalizable molecular coassembly strategy for enhancing type-I PDT and EMT regulation, offering a promising paradigm for next-generation antimetastatic phototherapeutic platforms with translational potential.