Oral Administration of Berberine-Based Carbon Dots Target Ferric Iron to Alleviate Atherosclerosis

Atherosclerosis (AS), a leading cause of cardiovascular morbidity and mortality, is characterized by aberrant iron accumulation within plaques. Iron overload exacerbates oxidative stress and promotes plaque instability through reactive oxygen species (ROS) generation, yet targeted iron chelation strategies remain underdeveloped. Whether and how iron homeostasis can be therapeutically modulated to impede AS progression represents an unresolved research question. In this study, berberine-derived carbon dots (BCDs) were developed as a nanotherapeutic agent that specifically chelates ferric ions to target iron dysregulation and oxidative stress, ultimately inhibiting AS progression. In the high-fat diet-fed ApoE^–/– mouse AS model, BCDs inhibited two-thirds of aortic plaque formation and alleviated the progression of AS through a dual mechanism involving antireactive oxygen species effects and ferric ion chelation. The experiment further compared the effects of different administration routes of BCDs on plaque formation. Oral administration enhances the effectiveness of BCDs compared with injections. The study revealed that oral administration of BCDs reduced ferric iron levels in AS plaques by 38%. Functioning as specific iron chelators, BCDs effectively bind Fe³⁺ at concentrations as low as 4 nM in foam cells. This iron-chelating activity significantly inhibits oxLDL uptake by macrophages, thereby suppressing foam cell formation. Our study identifies BCDs as an iron-targeting nanodrug that concurrently addresses oxidative stress and iron dysregulation in atherosclerosis. By elucidating a dual mechanism of action and demonstrating oral efficacy, we highlight the translational potential of BCDs as a promising therapeutic strategy for AS and other iron overload-related pathologies.