MicroRNAs as master regulators of macrophage function in atherosclerosis: From polarization to therapeutic potential

Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation, plaque formation, and calcification within large arteries, remains a leading cause of cardiovascular morbidity. This review integrates emerging evidence on the central role of microRNAs (miRNAs) as master regulators of macrophage biology in atherosclerosis pathogenesis. We highlight how miRNAs orchestrate macrophage polarization (e.g., miR-155 promotes the proinflammatory M1 phenotype; miR-126 facilitates the anti-inflammatory M2 phenotype), inflammatory responses (via NF-κB/TLR signaling), lipid metabolism (through the modulation of CD36 and ABCA1/ABCG1-mediated uptake/efflux), and programmed cell death (through apoptosis, autophagy, and ferroptosis). Therapeutically, targeting miRNA-mediated regulatory networks in macrophages offers unique potential to concomitantly ameliorate lipid accumulation, inflammation, and plaque vulnerability. However, translational challenges-including tissue-specific delivery, miRNA stability, and clinical validation-require innovative solutions such as engineered nanoparticles and combinatorial strategies. Advancing miRNA-based therapeutics may lead to the development of precision interventions for atherosclerosis beyond conventional approaches.