A targeted bimetallic MOF nanoparticle for doxorubicin delivery to enhance synergistic antitumor therapy

The clinical application of doxorubicin (DOX) is severely limited by its off-target toxicities and the emergence of chemoresistance when used alone. Herein, we engineered a chondroitin sulfate (CS)-targeted Mn-Fe bimetallic metal-organic framework nanoparticle loaded with DOX (SMFDC) that integrates chemotherapy and chemodynamic therapy (CDT) within a single platform. SMFDC exhibited uniform spherical morphology with a particle size of 164.5 ± 3.2 nm and a zeta potential of −9.11 ± 0.26 mV. The DOX encapsulation efficiency was 52.9 ± 3.54%, the drug loading capacity was 24.05 ± 1.4%, and the hemolysis rate was 1.08 ± 0.12%. The nanoparticle enabled pH/glutathione (GSH) dual-responsive release, achieving 60.33 ± 3.09% cumulative release of DOX within 60 h under simulated tumor microenvironment (TME) conditions (pH 5.0, 10 mM GSH). The released Mn 2+ /Fe 2+ ions efficiently catalyzed the Fenton/Fenton-like reaction to convert H 2 O 2 into hydroxyl radicals (·OH), while markedly depleting intracellular GSH and inducing potent oxidative stress. CS modification significantly enhanced cellular uptake in HeLa cells. In vitro antitumor evaluation showed that the half-maximal inhibitory concentration (IC 50 ) of SMFDC (DOX-equivalent) was 5.708 μg/mL, which was significantly lower than that of the unmodified SMFD group (12.849 μg/mL). Unlike previously reported Mn-Fe bimetallic MOFs used solely for CDT or CS-modified MOFs used only for targeting, this work integrates DOX loading, Mn-Fe bimetallic CDT, and CS-mediated active targeting into a single nanoplatform. This integrated design achieved synergistic chemotherapy-CDT, carrier-based pH/GSH dual-responsive release, and active tumor targeting, thereby enhancing CDT efficacy while overcoming the off-target toxicity and chemoresistance associated with DOX monotherapy. This strategy not only offers a promising paradigm for synergistic therapy but also provides a generalizable design principle for developing next-generation CDT-based combination nanomedicines. Download: Download high-res image (307KB) Download: Download full-size image