Targeted eradication of intratumoral Fusobacterium nucleatum via a cascade-responsive biomimetic nanoplatform for stemness reversal and chemotherapy potentiation

Breast tumors harbour intracellular Fusobacterium nucleatum that amplifies cancer stem cell (CSC) traits and chemoresistance. Coordinating intracellular bacterial eradication with stemness reversal to restore drug sensitivity remains a formidable therapeutic challenge. Here, we develop breast cancer cell membrane-cloaked calcium-phosphate nanoparticles (C/D-B-CaP@M) that sequentially deliver clindamycin phosphate (CDP) and doxorubicin (DOX). C/D-B-CaP@M efficiently targets F. nucleatum- infected CSC-like 4T1 cells. Upon internalization, C/D-B-CaP@M first releases CDP in response to the acidic intracellular microenvironment, effectively eradicating intracellular F. nucleatum , reversing stem-like properties, restoring ROS homeostasis, inhibiting epithelial-mmesenchymal transition and re-sensitising cells to chemotherapy. The elevated ROS then serves as an in situ trigger for on-demand DOX release for lethal cytotoxicity. C/D-B-CaP@M efficiently inhibits breast cancer progression and metastasis, offering a versatile, precision approach to dismantle microbiota-driven chemoresistance. A smart pH/ROS cascade-responsive biomimetic nanoplatform kills intratumoral Fusobacterium nucleatum firstly to revert tumor cell stemness, and then unleashes chemotherapy for precision breast cancer therapy.