Multiple Strikes Achieve Remarkable Tumor-Inhibition Efficiency <i>via</i> Multi-mechanism Combination.

Breast cancer treatment has been challenging all the time because cancer cells have multiple signaling pathways; so, breast cancer still remains a threat to the lives and health of many patients. While common single drug therapies inhibit only one pathway, the combination of multiple mechanisms offers the potential to simultaneously suppress multiple targets and pathways to kill cancer cells more effectively. It is reported that autophagy caused by autophagy inducers and apoptosis caused by some chemotherapeutic drugs can promote ferroptosis to some extent; herein, we combined these three pathways and constructed a multifunctional dual-responsive release nanosystem of Rap@mFe₃O₄-DOX-HA that achieved the ferroptosis-autophagy-apoptosis synergistic effect for cancer treatment. Mesoporous Fe₃O₄ (mFe₃O₄) was set as the carrier and can also release Fe ions for ferroptosis, the autophagy inducer rapamycin (Rap) was wrapped in the carrier to trigger autophagy, and the chemotherapeutic drug doxorubicin (DOX) was used as the apoptosis inducer. At the tumor site, the prepared Rap@mFe₃O₄-DOX-HA nanoparticles split and released DOX/Rap in response to H⁺/GSH. From <i>in vivo</i> and <i>in vitro</i> studies, it was found that Rap@mFe₃O₄-DOX-HA nanoparticles effectively inhibited the migration of 4T1 cells, furthermore, they struck cancer cells through multiple pathways and greatly improved the anti-tumor effect. Therefore, the strategy of multi-mechanism combination achieved a therapeutic effect of 1 + 1 &gt; 2.