LIFU-Responsive Nanocomplexes Deliver PDGF-BB mRNA for Plaques Stabilization via Neovascularization Modulation

BackgroundPathological intraplaque neovascularization, vascular leakage, and fibrous cap thinning contribute to vulnerable atherosclerotic plaque rupture. Platelet- derived growth factor-BB (PDGF-BB) has been shown to promote pericyte recruitment, thereby stabilizing the microvascular structure, and to induce phenotypic modulation of vascular smooth muscle cells (VSMCs), which enhances fibrous cap thickness and reinforces plaque stability. Nevertheless, systemic protein delivery is limited by rapid clearance and potential off-target effects. MethodsWe 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-/-Fbn1C1041G+/- mice. ResultsLIFU 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. ConclusionsLIFU-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. Research Perspective What New Question Does This Study Raise?O_LICan spatially controlled PDGF-BB mRNA delivery simultaneously mature intraplaque neovessels and reinforce the fibrous cap without the systemic effects associated with recombinant PDGF-BB? C_LI What Question Should Be Addressed Next?O_LIFuture studies should define the therapeutic window, durability, and long-term safety of LIFU-triggered PDGF-BB mRNA delivery in large-animal models that more closely reproduce human plaque rupture. C_LI