Hypoxia-amplifying polymer nanoprodrugs for sonodynamic chemotherapy for breast cancer and bone metastasis <i>via in situ</i> thrombogenesis

Reactive oxygen species (ROS)-producing treatment methods, such as sonodynamic therapy (SDT), usually exhibit limited efficacy for solid tumors because of the hypoxic tumor microenvironment. To address this challenge, we report a hypoxia-amplifying polymer nanoprodrug (DPTT) for breast cancer and bone metastasis therapy <i>via in situ</i> thrombogenesis to improve chemotherapy effects. The nanoprodrug (DPTT) was fabricated <i>via</i> co-loading a sonodynamic semiconducting polymer (SP) and a hypoxia-activated prodrug, tirapazamine (TPZ), into an ROS-responsive nanomicelle decorated with thrombin on the nanoparticle surface. After enrichment at tumor sites, DPTT can produce ROS under ultrasound exposure by the sonodynamic effect of SP for SDT, triggering ROS-responsive structural disintegration and subsequent controlled release of thrombin and TPZ. The liberated thrombin induces fibrin formation and <i>in situ</i> thrombogenesis in tumor tissues, disrupting vascular functions and oxygen supply to further intensify tumor hypoxia. As a consequence, TPZ prodrugs are activated in aggravated hypoxic regions to enable enhanced chemotherapeutic effects. Remarkably, this therapeutic approach is demonstrated to achieve near-complete eradication of subcutaneous 4T1 breast tumors and substantial inhibition of bone metastasis progression in murine models. Our work presents a novel vascular disruption strategy for hypoxia potentiation, offering a promising therapeutic paradigm for treating hypoxic solid and metastatic tumors.