Nanomedicine Targeting Macrophage Immunometabolism in Atherosclerosis: Mechanisms and Therapeutic Prospects

ABSTRACT Atherosclerosis, a chronic inflammatory–metabolic disorder, remains a leading cause of cardiovascular morbidity worldwide. This review explores the emerging paradigm of nanomedicine‐based targeting of macrophage immunometabolic reprogramming as a potentially transformative strategy for atherosclerosis treatment. We emphasize innovative approaches such as stimulus–responsive nanocarriers (e.g., pH‐, reactive oxygen species‐, or enzyme‐activated systems) for spatiotemporal drug delivery and metabolic modulation within plaques, and nanoplatforms for delivering genetic regulators (e.g., small interfering RNA or microRNA) for precise manipulation of key metabolic targets, including 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3 (glycolysis) and ATP‐binding cassette A1 (cholesterol efflux). Despite promising preclinical outcomes, clinical translation faces substantial challenges, including optimizing nanocarrier biocompatibility, achieving subtype‐specific targeting amid macrophage heterogeneity, and resolving scalability and standardization issues. Future advancements will require interdisciplinary collaboration integrating immunometabolism, materials science, and artificial intelligence to develop next‐generation nanotherapeutics, coupled with robust clinical validation to facilitate their translation into personalized therapies for atherosclerosis.