Vascular-Targeted Nanoplatform for Enhanced Immunotherapy via Synergistic Thrombosis and Hypoxia-Activated Chemotherapy

Tumor vasculature plays a crucial role in sustaining cancer progression, making vascular-targeted strategies highly promising for therapy. Herein, we develop a vascular-targeted nanoplatform (ThT@ZRR) that synergistically integrates thrombin-induced thrombosis with hypoxia-activated chemotherapy to amplify antitumor immunity. ThT@ZRR consists of thrombin and tirapazamine (TPZ) coloaded within ZIF-8 nanoparticles cloaked by RGD-modified red blood cell membranes. Upon tumor accumulation, pH-responsive thrombin release induces localized thrombosis, disrupting blood flow and exacerbating hypoxia, which, in turn, enhances TPZ activation. This cascade not only enhances direct tumor cell killing but also triggers robust immune responses. The combined effects of thrombosis-induced inflammatory signals and TPZ-mediated immunogenic cell death promote dendritic cell maturation, CD8+ T-cell infiltration, and pro-inflammatory macrophage polarization, fostering a tumor microenvironment conducive to immune activation. Notably, ThT@ZRR exhibited potent antitumor efficacy in murine melanoma (B16F10) and triple-negative breast cancer (4T1) models with distinct vascular architectures, highlighting its adaptability to heterogeneous tumor microenvironments. By integration of vascular embolization, hypoxia-activated chemotherapy, and synergistic thrombosis- and ICD-driven immune activation, this nanoplatform offers a promising strategy for enhancing cancer immunotherapy and overcoming immune resistance in solid tumors.