Dual-targeted fucoidan-TPP nanoparticles delivery system potently inhibit breast cancer via mitochondrial dysfunction and cGAS-STING activation.

Breast cancer remains a significant global health challenge, necessitating novel therapeutic strategies to overcome limitations such as drug resistance and systemic toxicity. Mitochondria play a crucial role in tumor apoptosis and immune regulation. This study developed a dual-targeted nanodelivery system, FU@TPP/PTE Mn²⁺ NPs, combining fucoidan (FU) for P-selectin-mediated tumor targeting and triphenylphosphine (TPP) for mitochondrial localization. The system co-delivered pterostilbene (PTE) and manganese ions (Mn²⁺) to enhance apoptosis and immune activation in breast cancer cells. The results demonstrated that FU@TPP delivery system could be delivered to cells through P-selectin and further localized in mitochondria, achieving the dual targeting function. Further in vitro results indicated that FU@TPP/PTE Mn²⁺ NPs induced mitochondrial related apoptosis and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in 4T-1 cells. In vivo studies in a 4T1 breast cancer model revealed significant tumor growth inhibition and reduced lung metastasis. The in vivo mechanism results confirmed that FU@TPP/PTE Mn²⁺ NPs activated the mitochondrial apoptosis pathway and cGAS-STING pathway, as well as enhanced dendritic cell maturation and CD8⁺ T cell infiltration. These findings highlight the potential of mitochondrial and immune pathway modulation for advanced breast cancer treatment.