The human aorta is a high-risk area for vascular diseases, which are commonly restored by thoracic endovascular aortic repair. In this paper, we report a promising shear-activated targeted nanoparticle drug delivery strategy to assist in the treatment of coarctation of the aorta and aortic aneurysm. Idealized three-dimensional geometric models of coarctation of the aorta and aortic aneurysm are designed, respectively. The unique hemodynamic environment of the diseased aorta is used to improve nanoparticle drug delivery. Micro-carriers with nanoparticle drugs would be targeting activated to release nanoparticle drugs by local abnormal shear stress rate (SSR). Coarctation of the aorta provides a high SSR hemodynamic environment, while the aortic aneurysm is exposed to low SSR. Results show that the upstream near-wall area of the diseased location is an ideal injection point for the micro-carriers, which could be activated by the abnormal SSR. Released nanoparticle drugs would be successfully targeted delivered to the aortic diseased wall. Besides, coarctation of the aorta would prevent blood flow to the descending aorta, while the effect of the aortic aneurysm on the blood flow distribution is negligible. This study preliminary demonstrates the feasibility of shear-activated targeted nanoparticle drug delivery in the treatment of aortic diseases and provides a theoretical basis for developing novel therapy.