Fibrinogen-Drug Nanoparticles Eradicate Pancreatic and Triple-Negative Breast Cancers in Mice

Abstract Poor intratumoral drug penetration and short-lived therapeutic exposure limit durable responses to cytotoxic therapies. We developed a strategy that redirects an evolutionarily optimized clotting cascade to achieve selective, sustained drug deposition within solid tumors. A vascular disrupting agent induces tumor-specific endothelial injury and platelet activation, exposing GPIIb/IIIa. Systemically administered fibrinogen–drug nanoparticles (FDNs) bind activated platelets with multivalent avidity, amplify thrombus formation, and become immobilized within tumor vessels, creating an intratumoral drug depot that maintained paclitaxel above cytotoxic levels for over 10 days. A single 15-minute treatment eradicated advanced triple-negative breast tumors in 88% of mice, while docetaxel-based FDNs produced durable eradication of pancreatic tumors in all treated mice (9/9). These findings establish a clinically translatable clot-guided platform for sustained therapeutic exposure in refractory cancers.