Neutrophil-Delivered Dual Stimuli-Responsive Cisplatin/Quercetin Nanodrugs for Breast Cancer Resistance Reversal.

Abstract

Cisplatin (CDDP) resistance remains a formidable obstacle in breast cancer treatment. To address this challenge, we engineered a neutrophil-mediated co-delivery system loaded with a Pt(IV) prodrug (Pt-HPBA) and quercetin (QC). A pH/glutathione (GSH)-dual-responsive nanodrug (Pt-HE@QC/NPs) was constructed via co-assembly of Pt-HPBA and QC. The resulting nanodrugs exhibited high drug loading capacity, maintained excellent colloidal stability under physiological conditions, and rapidly disassembled within the tumor microenvironment, enabling controlled drug release. These nanodrugs were then internalized by neutrophils to form a bio-hybrid delivery system (Pt-HE@QC/NEs). In vitro, Pt-HE@QC/NPs enhanced cellular uptake and exhibited potent cytotoxicity against cisplatin-resistant 4T1/DDP cells. The nanodrug reversed chemoresistance through multiple synergistic mechanisms: inducing mitochondrial dysfunction and reducing intracellular ATP levels to suppress efflux transporter activity; depleting GSH via phenylboronate ester cleavage and Pt(IV) reduction to amplify oxidative stress; and inhibiting GST-π and GPX4 activities to potentiate platinum-induced nuclear toxicity. In vivo, Pt-HE@QC/NEs demonstrated superior tumor-targeting capability and achieved remarkable tumor growth inhibition (TGI: 88.7%). Moreover, this treatment alleviated immunosuppression by triggering immunogenic cell death, enhancing CD8⁺ T cell infiltration, promoting M1 macrophage polarization, and elevating pro-inflammatory cytokine levels. Notably, systemic toxicity was significantly reduced compared to free CDDP. Collectively, this neutrophil-driven, dual-responsive nanoplatform represents a promising strategy for overcoming cisplatin resistance in breast cancer.