Potentiating Paclitaxel with its Homologous Nanovesicles: A Synergistic Strategy for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is highly invasive and has limited effective treatment options. Here, we developed natural extracellular nanovesicles derived from Taxus leaves (TLENs), which share the same plant origin as that of paclitaxel (PTX), to explore their potential as a targeted therapy carrier for TNBC. Through nontargeted metabolomics, it was found that it contains a large amount of flavonoids, with naringenin being the most abundant compound, as confirmed by LC-MS/MS analysis. Experiments have shown that the nanovesicles have significant anti-TNBC effects and, more importantly, can improve sensitivity to paclitaxel. At the cellular level, TLENs are internalized by TNBC cells via macropinocytosis, triggering an intracellular surge of reactive oxygen species that activates the JNK/p38 MAPK signaling cascade, thereby driving apoptosis while inhibiting cell proliferation, epithelial-mesenchymal transition, and migration. Beyond direct cytotoxicity, the oral coadministration of TLENs and PTX fundamentally remodeled the tumor microenvironment. The treatment effectively reversed immunosuppression by promoting dendritic cell maturation and enhancing cytotoxic CD8+ T cell infiltration while concurrently depleting regulatory T cells (Tregs) and myeloid-derived suppressor cells. This work innovatively proposes a "homologous combination" strategy that combines TLENs derived from the same plant with PTX. This combination exhibits enhanced anti-TNBC effects that are greater than those of either agent alone, providing a novel combination therapy for the treatment of TNBC.