A pH/H2O2 Dual-Responsive Cobalt–Manganese-Based Nano-Delivery System for Chemo/Chemodynamic Therapy in Triple-Negative Breast Cancer

Guanghui Mei,1 Fei Lin,1,2 Liying Huang,1 Min Lin,3 Xinhua Lin,1 Lingyi Huang1 1School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2College of Chemistry, Fuzhou University, Fuzhou, 350108, People’s Republic of China; 3School of Innovation, Entrepreneurship, and Creation of Minjiang University, Fuzhou, Fujian, 350108, People’s Republic of ChinaCorrespondence: Lingyi Huang, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email [email protected] Xinhua Lin, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email [email protected]: This study developed a dual-responsive nano-delivery system to overcome elevated glutathione (GSH) and acidic pH in the tumor microenvironment (TME), enhancing chemodynamic therapy (CDT) and chemotherapy against triple-negative breast cancer (TNBC).Methods: A pH/H2O2-responsive nanoplatform named as ZIF-67/MnO2/DOX/BSA/SDS (ZMDBS), was developed by integrating zeolitic imidazolate framework-67 (ZIF-67) with manganese dioxide (MnO2), loading doxorubicin (DOX), then introducing bovine serum albumin (BSA) and sodium dodecyl sulfate (SDS). Under TME conditions, it released Co²⁺ and Mn²⁺ ions to promote Fenton-like reactions and reactive oxygen species (ROS) generation. Physicochemical properties, GSH/H2O2 responsiveness, ROS production, and pH-triggered DOX release were also evaluated. In vitro (cellular uptake, ROS quantification, apoptosis, and migration tests) and in vivo experiments were conducted, alongside transcriptomic profiling.Results: Characterization results (particle size, zeta potential, FTIR, TEM, XRD, and XPS) confirmed ZMDBS as a novel cobalt/manganese-based nanocomposite, with the encapsulation rate of 95%. It efficiently depleted GSH, enhanced ROS production, and controlled DOX release under TME conditions. In vitro experiments, ZMDBS showed minimal toxicity to LO2 hepatocytes, whereas induced a two-fold ROS increase, 70.7% apoptosis in 4T1 cells (vs 40.9% for DOX), and a lower IC50 (0.35 μg/mL vs 5.00 μg/mL for DOX). In vivo, ZMDBS reduced tumor volume by 60.7% in mice without systemic toxicity (vs 31.1% for DOX). Transcriptomics revealed that ZMDBS-triggered ROS overproduction activated the p53, MAPK, and TNF pathways, culminating in caspase-mediated apoptosis.Conclusion: ZMDBS, a pH/H2O2 dual-responsive cobalt/manganese-based nanoplatform, has remodeled the TME for synergistic CDT and chemotherapy. With high catalytic efficiency and favorable biocompatibility, it offers a promising strategy for safe and effective TNBC treatment.Keywords: chemodynamic therapy, triple-negative breast cancer, tumor microenvironment, cobalt/manganese-based nano-delivery system, ZIF-67/MnO2/DOX/BSA/SDS