In recent years, targeted drug delivery systems have been regarded as a promising solution to enhance the efficiency of treatments against clots in blood vessels. In this context, shear‐activated nanotherapeutics (SANTs) have been recently proposed. These are micrometric clusters of polymeric nanoparticles coated with a clot lysing agent. These drug carriers are stable under normal blood flow conditions, but they can be designed to undergo breakup right on the clot in response to the local increase in the hydrodynamic stress caused by the lumen restriction, effectively concentrating the active agent at the point of need. The aim of this work is to investigate the mechanical response of three potential drug carrier morphologies to the pathological flow field stress, typically encountered in obstructed blood vessels. Computational fluid dynamics simulations have been used to compare the viscous stress in arterial obstructions with the one in a microfluidic device, suitable for in vitro experimental tests. Discrete element method simulations built upon Stokesian dynamics were conducted to estimate the tensile stress distribution acting inside isostatic, random close packing, and hollow drug carriers. The results herein presented constitute a platform for a future experimental campaign and aim at establishing SANTs as a robust and broadly applicable targeting strategy.

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