Abstract
BACKGROUND: Atherosclerosis (AS), the primary cause of cardiovascular morbidity and mortality, involves chronic vascular inflammation and plaque formation. While conventional therapies target systemic risk factors, their limited plaque-specific effects and adverse profiles have driven the exploration of targeted delivery systems. Nanoparticle-mediated delivery of nucleic acid therapies offers a promising strategy to modulate inflammation and promote plaque regression at the molecular level. This study aimed to systematically evaluate recent preclinical evidence on the effectiveness of functionalized nanoparticles for delivering nucleic acid-based therapies to atherosclerotic plaques. METHODS: This systematic review, conducted in accordance with the PRISMA 2020 guidelines, evaluated preclinical studies published between 2018 and 2024 that utilized nanoparticles to deliver siRNA, miRNA inhibitors, or antisense oligonucleotides (ASOs) to atherosclerotic plaques. Data extraction included nanoparticle type, targeting ligands, size, loading efficiency, administration route, and therapeutic outcomes. Comparative figures were generated, including a bar chart of plaque reduction efficacy by nanoparticle type and a qualitative heatmap mapping functionalization strategies to molecular targets. RESULTS: Fifteen animal studies met the inclusion criteria. Nanoparticles varied in size (5-190 nm), composition (cyclodextrin, gold, polymeric, lipid-based), and targeting mechanisms (e.g., VCAM1, CD36, integrin ligands). High efficacy was reported for functionalized carriers targeting macrophages or inflammatory pathways, with plaque reductions up to 65.8%. Visual analyses highlighted cyclodextrin-integrin and rHDL-based systems as top-performing strategies, while a heatmap revealed preferred pairings of delivery ligands with nucleic acid targets. CONCLUSION: Functionalized nanoparticles demonstrate robust preclinical efficacy for delivering nucleic acids to atherosclerotic plaques. These findings support their potential for targeted, multimodal therapy in cardiovascular disease, warranting further clinical investigation into scalable, biocompatible delivery platforms.