When blood clots form during atherosclerosis or a stroke, the obstruction increases the shear forces of blood in the blocked vessel. Researchers are now taking advantage of these forces to break apart nanoparticle clusters to deliver a clot-busting drug called tissue plasminogen activator (tPA) so that much less of the drug is required (Science, DOI: 10.1126/science.1217815). Because tPA causes serious side effects, such as excessive internal bleeding, the new delivery strategy has the potential to enhance drug safety, says Harvard University’s Donald E. Ingber, who led the research. Ingber’s team assembled aggregates of poly(lactic-co-glycolic acid) nanoparticles to which they attached tPA via a biotin linker. In normal blood flow, the aggregates remain intact. But near a blockage the increased shear forces break the aggregates apart, releasing the drug for efficient arrival at the clot site. Hurdles remain before the drug delivery system can enter the clinic, including ensuring nanoparticle safety and replacing biotin with a linker that doesn’t activate the human immune system.