pH-responsive sparfloxacin/Fe³⁺ nanoparticles eradicate intratumoral bacteria and activate ferroptosis for enhanced antitumor immunotherapy in breast cancer.

Abstract

Tumor-resident microbiotas critically influence breast cancer progression and metastasis. To simultaneously eliminate intratumoral bacteria and induce tumor cell death, we developed pH-sensitive nanoparticles (PEPCA@SPA/Fe³⁺ NPs) by encapsulating sparfloxacin (SPA)-ferric ion (Fe³⁺) nanoparticles (NPs) within an amphiphilic polyethylene glycol-poly (cinnamyl aldehyde) (PEPCA) copolymer assembly. The PEPCA@SPA/Fe³⁺ NPs exhibit dual functions including antibacteria and tumor ferroptosis induction. When PEPCA@SPA/Fe³⁺ NPs entered the acidic environment of tumor cells, SPA/Fe³⁺ NPs were released, which could effectively eradicate intratumoral bacteria and oxidize glutathione (GSH), thus inactivating glutathione peroxidase-4 (GPX4) and triggering lipid peroxidation and ferroptosis of tumor cells. In orthotopic breast cancer models, intravenously administrated PEPCA@SPA/Fe³⁺ NPs effectively accumulated in tumor tissues and suppressed primary tumor growth, and significantly reduced lung metastasis by remodeling the intratumoral microbiota. Furthermore, the PEPCA@SPA/Fe³⁺ NPs formulation well synergized with α-CD47 immunotherapy to activate antitumor immunity by promoting the maturation of dendritic cells (DCs), inducing M1 polarization of tumor-associated macrophages (TAMs), down-regulating regulatory T cells (Tregs) and enhancing cytotoxic T cells. Collectively, this nano-platform provides a promising strategy for concurrent microbial elimination and ferroptosis induction in cancer therapy.