An Atorvastatin/Ferrostatin-1 Codelivered Hybrid Exosome/Liposome System for Combinational Ferroptosis Inhibition, Inflammation Suppression, Efferocytosis Promotion, and Macrophage Reprogramming in Atherosclerosis Treatment

The development of atherosclerosis (AS) triggers a subsequent series of cardiovascular complications, greatly threatening people's health. Cholesterol-lowering drugs represented by statins are commonly used anti-AS options, the efficiency of which is largely limited by their first-pass effects and poor plaque-targeting capacity. In addition, given the complexity of AS, statin treatment alone hardly exerts an ideal curative effect. Therefore, therapeutic systems for AS-specific statin-based combination therapy are urgently needed. Based on the characteristics of AS lesions, we innovatively propose to combine ferroptosis inhibitors with statins, simultaneously reprogramming macrophage differentiation in the AS microenvironment. As a proof of concept, we herein report a biomimetic plaque-targeting M2-exosome (E)/liposome (L) nanohybrid coencapsulated with atorvastatin (A) and ferrostatin-1 (F) (named EL@AF), which exhibits desirable anti-AS efficiency in vitro and in vivo by integrating plaque-targeting, anti-inflammatory, cholesterol-effluxing, ferroptosis-inhibiting, macrophage-reprogramming, and efferocytosis-promoting effects. Interestingly, ferrostatin-1, besides inhibiting ferroptosis, also promotes macrophage efferocytosis, the mechanisms of which might be related to MAPK pathway activation, as our preliminary research results suggested. Taken together, this study reports a therapeutic system for robust comprehensive AS treatment, wherein drug combination modes and mechanisms are proposed, driving the potential application of ferrostatin-1 as a subsidiary anti-AS agent and providing an attractive avenue for advanced AS treatment.