Abstract
<jats:p> Background: Pathological intraplaque neovascularization, vascular leakage, and fibrous cap thinning contribute to vulnerable atherosclerotic plaque rupture. Platelet-derived growth factor-BB (PDGF-BB) promotes mural-cell recruitment and vascular stabilization, but systemic protein delivery is limited by rapid clearance and potential off-target effects. Methods: We developed PDGF-BB mRNA-loaded lipid nanoparticle-poly(lactic-co-glycolic acid) nanobubble complexes (LNPmRNA@PLGA) and used low-intensity focused ultrasound (LIFU) to enhance plaque-targeted delivery. Cellular uptake, PDGF-BB expression, vascular mural-cell responses, plaque histology, hemodynamics, and proteomic changes were evaluated in vitro and in ApoE <jats:sup>-/-</jats:sup> Fbn1 <jats:sup>C1041G+/-</jats:sup> mice. Results: LIFU enhanced nanocomplex uptake and PDGF-BB expression, promoted vascular smooth muscle cell proliferation, migration, and phenotypic switching, and increased pericyte coverage. In vivo, LIFU plus LNPmRNA@PLGA reduced the plaque vulnerability index by 78.2% and the neovascularization area by 67.3% compared with controls, while increasing collagen deposition and improving carotid hemodynamics. Conclusions: LIFU-responsive delivery of PDGF-BB mRNA stabilized vulnerable plaques by promoting neovessel maturation and strengthening the fibrous cap. This strategy provides a spatially controlled framework for therapeutic remodeling of high-risk atherosclerotic plaques. </jats:p>