Hierarchical Core−shell Nanoplatforms for pH-Triggered Drug Release and Enhanced Chemodynamic Cancer Therapy

Chemodynamic therapy (CDT) has emerged as a promising noninvasive strategy that catalyzes the conversion of endogenous substrates into highly reactive hydroxyl radicals (•OH) to induce cancer cell death. However, its clinical application is limited by insufficient•OH generation and the complexity of the tumor microenvironment (TME). Herein, we developed a biodegradable PEGylated core shell nanoplatform loaded with doxorubicin (PMSC-DOX NCs) for pH-responsive drug delivery and enhanced CDT. The Co9S8 core provides additional cobalt-based redox-active sites, and the reversible Co2+/Co3+ redox couples contribute to H2O2 activation and•OH generation, thereby improving the CDT efficiency of the PMSC−DOX NCs. The PMSC-DOX NCs enable efficient DOX encapsulation, while PEGylation enhances colloidal stability and prolongs blood circulation. Under acidic TME conditions, the nanoplatform undergoes structural degradation, triggering controlled drug release. Meanwhile, MnO2 reacts with endogenous H2O2 to generate O2 and is reduced to Mn2+, which subsequently participates in a Fenton-like reaction to generate cytotoxic reactive oxygen species (ROS). In vitro studies demonstrate enhanced cellular uptake, prolonged intracellular retention, and significantly improved cytotoxicity as compared to free DOX. The synergistic effects of chemotherapy and CDT lead to amplified oxidative damage and enhanced cancer cell apoptosis. This work offers a promising strategy for designing multifunctional nanoplatforms for enhanced cancer therapy.