Nanoplatforms have been used extensively as advanced carriers to enhance the effectiveness of drug delivery, mostly through passive aggregation provided by the enhanced permeability and retention effect. Mechanical stimuli provide a robust strategy to bolster drug delivery performance by increasing the accumulation of nanoplatforms at the lesion sites, facilitating on-demand cargo release and providing theranostic aims. In this review, we focus on recent advances of mechanoresponsive nanoplatforms that can accomplish targeted drug delivery, and subsequent drug release, under specific stimuli, either endogenous (shear stress) or exogenous (magnetic field and ultrasound), to synergistically combat atherosclerosis at the molecular level.