Dual‐Stage Drug Delivery Microspheres Amplify Tumor Starvation Through Coagulation‐Enhanced Vascular Occlusion

Tumor starvation therapy aims to deprive tumors of essential nutrients but is often hindered by incomplete vascular occlusion and tumor metabolic adaptation. In this study, a pH-responsive calcium carbonate (CaCO₃) embedded porous poly (lactic-co-glycolic acid) (PLGA) microsphere is developed to co-deliver the small-molecule vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and thrombin, synergistically inducing cascaded intravascular coagulation and enhancing the efficacy of tumor-starvation therapy. The incorporation of CaCO₃ nanoparticles not only increased the drug loading capacity but also endowed the microsphere with pH-responsiveness, enabling the sequential release of DMXAA under acidic conditions to disrupt blood vessels and induce procoagulant factors exposure, followed by the release of thrombin, which, in combination with the Ca²⁺ ions generated from the decomposition of CaCO₃, further promoted blood clotting. In vascularized B16F10 murine melanoma models, these engineered microspheres demonstrate significant therapeutic potential through targeted induction of tumor-associated intravascular thrombosis, resulting in marked anti-tumor efficacy. Notably, in orthotopically implanted 4T1 mammary carcinoma models, the multifunctional particulates not only achieve primary tumor growth retardation but also effectively mitigate pulmonary metastatic dissemination. Thus, this work highlights a functional microsphere with sequential drug release capabilities, which can synergistically amplify tumor coagulation, leading to enhanced tumor-starvation therapy.