Systemic administration of thrombolytic drugs can restore disrupted blood flow caused by ischemic stroke or pulmonary embolism. However, when diffusing freely throughout the body, these agents can also cause dangerous bleeding. Korin et al. devise a new therapeutic strategy to target thrombolytic activity to occluded vessels. Knowing that fluid shear stress can be orders of magnitude higher in constricted compared with normal vessels, the authors fabricate microscale nanoparticle aggregates cued to break apart into smaller nanoparticles upon exposure to pathologically high local shear stress. Subjected to lower drag forces than their microscale precursors, the smaller nanoparticles can adhere more efficiently to substrates such as endothelial cells and clots. When coated with the thrombolytic drug tissue plasminogen activator (tPA), these platelet biomimetics accumulated in regions of vascular occlusion and eroded clots in mouse models of arterial thrombosis and pulmonary embolism. Because they are effective at 100-fold lower doses than soluble tPA, are rapidly cleared from the circulation and can in theory be coated with a variety of thrombolyic agents, these shear-activated nanotherapeutics hold promise for treating a range of disorders associated with vascular obstruction. (Science advance online publication, doi:10.1126/science.1217815, 5 July 2012)