A MOF-based nanobomb for tumor microvascular occlusion and combined tumor starvation therapy and chemotherapy

As an important approach of tumor starvation therapy, vascular blockage has been widely studied and used in cancer therapy. Recently, thrombin, a common endogenous coagulation protease, has been adopted in cancer starvation therapy. However, intravenous injection of thrombin can cause severe toxicity to the body and single cancer starvation therapy always exhibits limited therapeutic effect. Here, we utilized a type of acid-responsive metal–organic framework (MOF) material (zeolitic imidazolate framework-8, ZIF-8) to encapsulate thrombin and doxorubicin (DOX) for realizing tumor microenvironment-triggerable tumor starvation-chemo combination therapy without the requirement of external stimuli. The as-designed material (termed TD@Z) displayed proper size, nanopopcorn morphology, and significant coagulation effect under pH 6.5 condition. In vitro cellular experiments revealed that the TD@Z "nanobomb" exhibited increased cell endocytosis and could achieve lysosomal escape, thus resulting in strong cell apoptosis. Moreover, superb tumor microvascular blockage and tumor inhibition effects were demonstrated via blood flow imaging and tumor vessel immunofluorescence staining experiments. Further, restricted blood flow could lead to local drug accumulation, thereby enhancing the chemotherapeutic effect of TD@Z. This work may promote the practical use of thrombin in cancer nanotherapy and inspire the design of other enzyme-incorporated MOF-based nanodrugs.