Inflammation-targeted nanoparticles modulate macrophage polarization for coronary therapy in Kawasaki disease

Coronary artery lesions are a major complication of Kawasaki disease (KD), where the local microenvironment is marked by excessive oxidative stress and persistent inflammation, presenting significant challenges for effective treatment. M1-polarized macrophages dominate these lesions, releasing pro-inflammatory mediators that aggravate vascular injury. Regulating macrophage polarization from the M1 to M2 phenotype thus offers a promising therapeutic strategy. Here, we developed a Reactive Oxygen Species (ROS)-responsive nanoplatform, HA-Sim@BRPL, to deliver simvastatin (Sim) specifically to inflamed coronary tissues. The nanocarrier is constructed from poly-l-lysine conjugated with bilirubin (BR), which self-assembles and enables ROS-triggered Sim release through BR's oxidative conversion to hydrophilic biliverdin. Surface decoration with hyaluronic acid (HA) facilitates selective uptake by CD44-expressing macrophages rather than cardiomyocytes. HA-Sim@BRPL effectively reduces intracellular ROS, promotes M2 macrophage polarization, and enhances endothelial cell survival via intercellular signaling. In a KD mouse model, HA-Sim@BRPL significantly attenuated coronary artery lesions and improved cardiac function. These results highlight a rationally designed nanomedicine that integrates oxidative stress responsiveness and inflammatory cell targeting, providing a promising therapeutic approach for coronary complications in KD.