Furin-responsive aggregable gold nanoparticles synergize chemo-immunotherapy against multidrug-resistant breast cancer

Multidrug resistance (MDR) and immunosuppression remain critical challenges in breast cancer therapy. Here, we report a size-tunable gold nanoparticle-based drug delivery system (AuNPs-DOX-RK&CABT) integrating chemotherapy, MDR reversal and macrophage repolarization. The dual-component system triggered furin-responsive click condensation reactions in tumors, inducing gold nanoparticles (AuNPs) aggregation to enhance tumor retention and intracellular acid-responsive doxorubicin (DOX) release. By inhibiting P-glycoprotein-mediated drug efflux and autophagy, the system overcame MDR while repolarizing M2-like tumor-associated macrophages (TAMs) to pro-inflammatory M1 phenotypes. In vivo studies in MCF-7/ADR tumor models demonstrated that AuNPs-DOX-RK&CABT significantly suppressed tumor growth, induced extensive necrosis/apoptosis, and modulated the immune microenvironment. This chemo-immunotherapeutic strategy integrated acid-responsive drug release, MDR reversal, and immune microenvironment modulation, offering a promising approach for MDR breast cancer treatment. Download: Download high-res image (468KB) Download: Download full-size image