Dual delivery of metformin and doxorubicin via the gum acacia-gelatin nanohydrogel disrupts tunnelling nanotube-mediated breast cancer progression.

Tunneling nanotubes (TNTs) are nano-scale intracellular conduits facilitating the transfer of cellular content. Intercellular communication between cancer cells via TNTs promotes invasion and metastasis. Given the important role of TNTs and macrophages in cancer, the role of macrophage-induced TNTs in the co-delivery of metformin (MET) and the chemotherapeutic drug doxorubicin (DOX) in mediating drug resistance is not fully understood. In this study, the inhibition of TNT-mediated breast cancer progression was mechanistically explored through DOX/MET co-delivery. For cargo delivery, the co-drugs were loaded onto gelatin and gum acacia. The DOX/MET co-loaded nanohydrogel induced the most substantial reduction in cell viability in MCF-7 breast cancer cells. The combination of DOX-MET resulted in the robust activation of caspase-3, indicating the enhanced execution of apoptosis. Upon internalization and lysosomal release, MET activates AMPK signaling, which in turn suppresses the PI3K/AKT/mTOR axis and inhibits TNT formation, thereby blocking intercellular communication. Concurrently, DOX localizes to the nucleus, where it disrupts DNA replication and directly induces cytotoxicity. This combined approach not only targets proliferative capacity but also dismantles cellular networking mechanisms. Overall, the results of this study endorse that this combined therapeutic strategy might offer enhanced efficacy in limiting breast cancer progression and metastasis through the inhibition of TNTs.