Abstract

Triple-negative breast cancer (TNBC) is characterized by aggressive biological behavior, including rapid post-treatment recurrence propensity, heightened metastatic dissemination, and significantly diminished survival outcomes. These features emphasize the necessity for innovative therapeutic strategies in TNBC treatment. Herein, we developed selenium nanoparticles modified with a mushroom polysaccharide-protein complex (PTR-SeNPs) and evaluated them in vitro anti-tumor efficacy across 17 human TNBC cell lines, followed by elucidation of the mechanism underlying PTR-SeNPs-induced apoptosis. In vitro evaluation across TNBC cell models revealed that PTR-SeNPs exhibit promising anti-tumor efficacy with preferential induction of mitochondrial-dependent apoptosis, demonstrating significant cytotoxic efficacy through MAPKs/Bcl2 pathway. Notably, further conjugation of PTR-SeNPs with anti-human MUC1 antibodies generated dual-modified nanoparticles (MUC1@PTR-SeNPs), which significantly enhanced anti-tumor activity in five TNBC cell lines with high/medium MUC1 expression. Furthermore, oral administration of MUC1@PTR-SeNPs for 30 days markedly inhibited tumor growth in mice bearing MDA-MB-468 xenografts via induction of mitochondria-mediated apoptosis. This work highlights the therapeutic potential of PTR-SeNPs against human TNBC, elucidates their molecular mechanisms, metabolic profile, and toxicity, thereby advancing this novel nano-mineral as a future treatment strategy for TNBC.