A drug-free, engineered hybrid exosome platform alleviates atherosclerosis via inflammation modulation and phenotype remodeling.

Elevated concentrations of reactive oxygen species (ROS) within the atherosclerotic microenvironment initiate positive feedback loops involving inflammatory mediators, consequently triggering an inflammatory storm between endothelial cells and macrophages. Currently, the treatment of atherosclerosis (AS) mainly focuses on removing lipids, without effective anti-inflammatory and antioxidant therapies. AgNPs with anti-inflammatory and ROS-scavenging functions demonstrate promising therapeutic effects against inflammation. Here, given the acidic microenvironment and inflammatory characteristics of the disease, we proposed a drug-free, engineered hybrid exosome platform (Lipo/exo-AgNPs) by fusing pH-sensitive liposomes with M2-type macrophage-derived exosomes (M2-exo) to encapsulate silver nanoparticles (AgNPs). Leveraging the messenger functions and inflammatory homing properties of M2-exo, Lipo/exo-AgNPs can maintain stable circulation in the blood and specifically target damaged endothelial cells and inflammatory macrophages within plaques. In vitro studies demonstrated that Lipo/exo-AgNPs exhibited enhanced uptake efficiency in both damaged endothelial cells and inflammatory macrophages. In ApoE-/- mouse model, treatment with the preparation significantly attenuated atherosclerotic plaque deposition and suppressed inflammatory responses. In conclusion, Lipo/exo-AgNPs effectively addressed the insufficient targeting specificity of traditional exosome delivery systems. Moreover, Lipo/exo-AgNPs not only enabled intelligent, controlled, and responsive drug delivery, but also elevated atherosclerosis treatment from a simple lipid-lowering strategy to a new level of microenvironment remodeling through a "triple synergistic enhancement" mechanism involving inflammation targeting-endothelial repair-phenotype reprogramming.