A pH/H₂O₂ Dual-Responsive Cobalt-Manganese-Based Nano-Delivery System for Chemo/Chemodynamic Therapy in...

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).

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.

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.

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.