Abstract
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to its aggressive nature, high metastatic potential, and lack of effective targeted therapies. Apigenin, a dietary flavonoid with well-documented anti-cancer properties, suffers from poor aqueous solubility and limited bioavailability, hindering its therapeutic translation. Here, we evaluate apigenin-loaded exosome-like vesicles (Apig-exo) as a biologically compatible nanocarrier to enhance apigenin's efficacy in TNBC. Exosome-like vesicles (EVs) were successfully engineered via sonication, achieving an encapsulation efficiency of 58.3% and a drug loading capacity of 5.2 µg/mg protein, with retained vesicle stability (122 nm, - 20 mV zeta potential, 68.2% CD63+). In vitro, Apig-exo significantly reduced MDA-MB-231 TNBC cell viability to 48.2% versus 72.0% for free apigenin, and elicited robust apoptosis (89.23% total, 82.8% early apoptosis). Mechanistically, Apig-exo suppressed oncogenic miR-155 expression (2.8-fold), restoring SOCS1 (3.8-fold) and VHL (3.3-fold), and upregulated tumor-suppressive miR-146a (3.2-fold), leading to downregulation of NF-κB mediators IRAK1 (3.1-fold) and TRAF6 (2.7-fold). Importantly, Apig-exo reactivated epigenetically silenced BRCA1 and STING genes through promoter demethylation, increasing their expression by 3.7-fold and 4.1-fold, respectively. Multivariate analyses, including PCA and hierarchical clustering, confirmed that Apig-exo induces a systems-level reprogramming of TNBC cells toward a less aggressive, more immunogenic state. These integrated molecular effects were superior to those of free apigenin or blank EVs. Collectively, our findings highlight Apig-exo as a potent, multi-modal therapeutic platform capable of overcoming TNBC resistance via coordinated modulation of microRNA networks, apoptotic pathways, and epigenetic landscapes.