Flexible Ultrasound Patch for Noninvasive, Targeted Anti-Angiogenic Therapy of Unstable Carotid Plaques

Purpose: The growing global burden of ischemic stroke highlights the need for a deeper understanding of its pathogenic mechanisms. Although carotid plaque destabilization driven by intraplaque neovascularization is recognized as a critical factor of cerebrovascular disease, therapeutic strategies targeting this mechanobiological process remains inadequately explored. This study aims to develop and validate a noninvasive, portable ultrasound-guided nanotherapy system for enhancing the stability of early carotid artery plaques. Methods: We investigated a theranostic approach combining ultrasound-mediated microbubble cavitation with nanoliposomal drug delivery, a strategy that requires precise parameter optimization to achieve localized anti-angiogenic effects within unstable plaques. Results: By engineering a flexible ultrasound device with adjustable power settings, we systematically demonstrated that combinatorial microbubble-nanoliposome treatment produces power-dependent therapeutic outcomes. Compared to the other groups, the microbubble-targeted liposome complex with ultrasound (MLCP + US) group demonstrated a marked reduction in necrotic core area, accompanied by increased collagen deposition and a pronounced decrease in intraplaque hemorrhage. Quantification of neovascularization via CD31 immunohistochemistry revealed near-complete suppression of intraplaque microvessels in the MLCP + US group. Western blot analysis further showed that the MLCP + US treatment significantly downregulated the expression levels of the examined signaling proteins. Multimodal analysis elucidated the mechanotransductive pathways by which ultrasound enhances drug penetration and promotes neovessel regression in preclinical models of carotid atherosclerosis. Conclusions: This study establishes a parameter-optimized, noninvasive platform for plaque stabilization and provides mechanistic insights that may inform the development of translationally relevant preventive strategies in stroke medicine.