Biotactic Nanodrugs Induce Tumor-Localized and Durable Embolization via Programmatic Participation in Physiological...

The clinical application of tumor vascular obstruction therapy (TVOT) is mainly hindered by imprecise obstruction localization and transient embolic effects. We developed a biotactic nanodrug termed PDA-A@Fib to achieve precise and sustained TVOT by programmatically participating in the physiological biochemical reactions related to the coagulation-fibrinolysis axis. Composed of a polydopamine (PDA) core loaded with aminomethylbenzoic acid (AA) and coated with fibrinogen (Fib), PDA-A@Fib was recruited to the tumor site following DMXAA-primed vascular damage via Fib-platelet interactions. Subsequently, thrombin converted the Fib coating to fibrin, seamlessly integrating the nanodrug into the evolving thrombus through crosslinking with endogenous fibrin. The dual reinforcement through the fibrin network and PDA cohesion conferred exceptional stability to the thrombus. Furthermore, the sustained release of AA confined within the thrombus inhibited plasmin, conferring robust resistance to fibrinolysis. This programmed engagement with the hemostatic cascade resulted in durable, tumor-localized vascular occlusion, achieving inhibition rates of 96.67% in early-stage and 87.09% in advanced-stage subcutaneous breast cancer models, respectively. In an orthotopic model, this strategy ensured a survival rate exceeding 80% over 65 days, demonstrating superior efficacy to conventional TVOT and showcasing the rational hijacking of innate biological pathways for safe and potent therapy.