Translational selenium nanoparticles trigger apoptosis in triple-negative breast cancer cells through the MAPKs/Bcl2 pathway

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. In this paper, mushroom polysaccharide-protein complex-modified selenium nanoparticles (PTR-SeNPs) were developed and analyzed for their in vitro antitumor efficacy against 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. Apart from enhancing the anti-proliferation activity against five TNBC cell lines, dual modified MUC1@PTR-SeNPs (further conjugation of PTR-SeNPs with anti-human MUC1 antibodies) was found to significantly improve their tumor inhibition effect on BALB/c nude mice transplanted with MDA-MB-468 xenograft after oral administration for 30 days. This study not only demonstrates the therapeutic potential of PTR-SeNPs against human TNBC but also clarifies their molecular mechanisms, metabolic profile, and toxicity, thereby advancing this novel nano-mineral as a future TNBC treatment strategy. • PTR-SeNPs exhibit promising anti-tumor efficacy against TNBC in vitro and in vivo. • PTR-SeNPs induce TNBC cell death through activation of mitochondria-mediated apoptotic pathway. • PTR-SeNPs are rapidly uptaken by TNBC via endocytosis and undergone specific metabolic biotransformation. • MUC1@PTR-SeNPs suppressed the growth of both cultured TNBC cells and MDA-MB-468 xenograft tumors.