A multifunctional metal-organic framework nanosystem disrupts redox homeostasis for synergistic therapy

Synergistic therapies of photodynamic therapy (PDT) and chemodynamic therapy (CDT) via metal-organic frameworks (MOF) for cancer treatment have recently attracted a lot of attentions because of the limitations of insufficient reactive oxygen species (ROS) in single-modality approaches. However, few studies explored on the use of increased ROS synergized with chemotherapy (CT) to address the issue of inadequate anti-tumor efficacy in single-modality regimens. Here, the desired cascade nanoplatforms (noted as MOF(Cu)@Dox-PL NPs) were fabricated by a solvothermal method using tetrakis (4-carboxyphenyl) porphyrin (TCPP) and zirconyl(di)chloride octahydrate (ZrOCl₂·8H₂O) as raw material, followed by Cu²⁺ introduced into the porphyrin ring and doxorubicin (DOX) loaded into the nanoframework. In addition, the nanoparticles (NPs) were electrostatically and hydrophobically coated with phospholipid (PL) to improve the biocompatibility of the nanosystems. Singlet oxygen (¹O₂) was created by the MOF(Cu)@Dox-PL NPs to disturb intracellular redox equilibrium. The acidic microenvironment in cancer cells may cause the prior release of DOX, which encourages the production of hydrogen peroxide (H₂O₂). And the doped Cu²⁺ could deplete overexpressed reduced glutathione (GSH) to produce hydroxyl radicals (·OH) by catalyzing H₂O₂, further causing redox dyshomeostasis. In vivo experiments revealed that MOF(Cu)@Dox-PL nanosystem possessed good biosafety and a compelling therapeutic effect in 4T1 tumor-bearing mice. As a novel nanosystem, MOF(Cu)@Dox-PL NPs showed great potential in synergistic therapy based on redox dyshomeostasis for improving anti-tumor efficacy with high specificity.