Ferroptosis-based nano-assembly enhanced breast cancer therapy by inhibiting intratumor bacteria

Intratumoral bacteria, especially Gram-positive bacteria (G+), have a unique bacterial niche in breast cancer that promoted tumor progression. However, the effects of G+ have so far been overlooked, serving an "invisible driver" of breast cancer. Moreover, due to the altered biological structure of G+ in tumor cells and the penetration barrier of antibiotics, the effect of antibiotic-mediated eradication of G+ in tumors is limited. Here, to simultaneously inhibit intratumoral G+ and tumor cells via ferroptosis therapy, an amorphous nano-assembly (DFTV) was constructed by assembling doxorubicin (DOX), tannic acid (TA), FeSO4, and vancomycin (Van). DFTV treatment effectively targets intratumoral G+, thereby inhibiting the growth of the breast tumor and postoperative recurrence by downregulating the expression of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Moreover, inhibiting intracellular G+ also restrains the reorganization of F-actin to form pseudopodia, thereby impairing tumor cell motility and blocking metastasis. Collectively, DFTV improves the antitumor efficacy by targeting G+ in breast tumors, offering novel insights into overcoming the limitations associated with the lack of intratumoral antibacterial therapy in clinical breast cancer treatment protocols.