Degradable co-delivery nanoplatforms for inflammation-targeted therapy against atherosclerosis

Abstract Atherosclerosis is characterized by chronic inflammation of the arterial wall. Activated macrophages play a significant role in the inflammatory process of atherosclerosis by secreting inflammatory factors such as interleukin-1 (IL-1) and interleukin-6 (IL-6). Among all the several methods to treat atherosclerosis, anti-inflammatory therapy with copper ions and IL-1 receptor antagonist (IL-1Ra) are the most promising approaches, but they are limited by side effects on liver damage and the short in vivo half-life of IL-1Ra, respectively. Herein, we developed an inflammation-targeted nanoplatform, i.e. IL-1Ra-loaded copper-doped mesoporous silica nanoparticles (IL-1Ra@Cu-MSNs), for co-delivery of IL-1Ra and copper ions. The nanoplatform showed outstanding drug-loading efficiency, sustained release property and biodegradability. Released copper ions specifically induced macrophage apoptosis by triggering ROS production. The loaded IL-1Ra conferred IL-1R-targeting and anti-inflammatory properties to the nanoplatform. In vivo study revealed that the IL-1Ra@Cu-MSNs significantly reduced arterial stenosis, plaque burden and macrophage infiltration due to the combined action of copper ions and IL-1Ra. Our work demonstrates that integration of targeted modulation of cellular function and inhibition of inflammation based on MSNs significantly alleviates arterial inflammation, which provides a novel strategy for the inflammation-targeted therapy against atherosclerosis.