Tunneling nanotubes (TNTs) are nanoscale intracellular conduits that mediate direct intercellular transfer of cellular content. In cancer, TNTs contribute to invasion, metastasis, and adaptive responses including drug resistance. Macrophages can enhance TNT formation and thereby influence tumor cell communication and behavior. Given the dual roles of TNTs and tumor-associated macrophages in promoting breast cancer progression, strategies that combine cytotoxic therapy with disruption of TNT-mediated networking may offer improved efficacy.
This study examined whether combined delivery of the antidiabetic agent metformin (MET) and the anthracycline doxorubicin (DOX) via a biopolymer nanohydrogel could inhibit TNT-mediated breast cancer progression while producing cytotoxic effects.
The investigators prepared a nanohydrogel based on gum acacia and gelatin as the carrier matrix and loaded it with both MET and DOX. The co-loaded formulation—referred to as the DOX/MET co-loaded nanohydrogel—served as the platform to deliver both agents concurrently to breast cancer cells. Specific formulation parameters, loading efficiencies, and physicochemical characterization details were not reported in the abstract.
After internalization of the nanohydrogel by MCF-7 breast cancer cells, intracellular trafficking resulted in lysosomal release of cargo. Once released from lysosomes, MET and DOX followed distinct intracellular destinies: MET engaged cytoplasmic signaling pathways, while DOX localized to the nucleus. The abstract does not provide quantitative uptake or release kinetics but describes these localization patterns as mechanistically relevant to therapeutic action.
Lysosomally released MET activated the AMP-activated protein kinase (AMPK) signaling axis. Activation of AMPK downstream led to suppression of the PI3K/AKT/mTOR pathway. Through this signaling modulation, MET contributed to inhibition of processes that support cell survival, proliferation, and TNT biogenesis. The abstract links AMPK activation directly to suppression of PI3K/AKT/mTOR and subsequent inhibition of TNT formation, but it does not present specific signaling fold-changes or time-course data.
Suppression of the PI3K/AKT/mTOR axis was associated with inhibition of TNT formation, thereby reducing intercellular communication among cancer cells. Because TNTs facilitate transfer of mitochondria and other cargo that can promote invasiveness and resistance, disrupting TNT networks represents a distinct antimetastatic mechanism complementary to direct cytotoxicity. The abstract notes the role of macrophage-induced TNTs in disease progression as part of the rationale, but experimental details regarding macrophage co-culture or conditioned media exposures were not provided in the abstract.
The DOX/MET co-loaded nanohydrogel induced the most substantial reduction in cell viability in MCF-7 breast cancer cells compared with other conditions tested. Concurrently, the combination produced robust activation of caspase-3, indicating enhanced execution-phase apoptosis. Mechanistically, DOX localization to the nucleus disrupted DNA replication and exerted direct cytotoxicity on proliferative tumor cells, while MET-mediated signaling changes reduced survival signaling and TNT formation, augmenting overall cell killing.
By combining a metabolic modulator (MET) with a DNA-damaging chemotherapeutic (DOX) in a gum acacia–gelatin nanohydrogel, the investigators report a dual-action approach: direct cytotoxicity through nuclear DOX and suppression of TNT-mediated cellular networking through MET-induced AMPK activation and PI3K/AKT/mTOR inhibition. The result was enhanced apoptosis and a pronounced reduction in MCF-7 viability. These findings support the concept that co-delivery strategies that both kill tumor cells and dismantle intercellular communication may limit breast cancer progression and metastasis.
The abstract does not provide detailed quantitative results, in vivo validation, toxicity profiling, or formulation characterization; those details would need to be consulted in the full text for assessment of translational potential.
Title: Dual delivery of metformin and doxorubicin via the gum acacia-gelatin nanohydrogel disrupts tunnelling nanotube-mediated breast cancer progression
Authors: Soumya Ranjan Jena, Anwesha Pradhan, Ganeswar Dalei, Subhraseema Das, Luna Samanta et al.
Journal: Biomaterials Science. 2026 Sep 29;14(19):5170-5185.
PMID: 42605874. DOI: 10.1039/d6bm00697c.
Note: This summary is based solely on the abstract and bibliographic metadata; specific experimental parameters, quantitative data, and extended results are not reported in the source abstract and require consultation of the full article for comprehensive evaluation.