A multi-target and responsive nanoplatform (MM/ZnS/ATV) combining H2S and atorvastatin for enhanced atherosclerosis therapy

Atherosclerosis, a chronic inflammatory disease characterized by the formation of atherosclerotic plaques in the arterial walls. The pathological process of atherosclerosis mainly contains lipid metabolism disorder, endothelial dysfunction, and progressive inflammation. Given the complexity of pathological process, treatments based on a single target might have very limited therapeutic efficacy. Thus, developing a nanoplatform to obtain an enhanced multi-target therapy is promising. Hydrogen sulfide (H2S) has various functions including anti-inflammation, anti-oxidation and endothelial protection. In this study, a responsive multi-target nanoplatform (MM/ZnS/ATV) combining the functions of H2S and atorvastatin was developed. The acidic microenvironment of the plaque can accelerate ZnS hydrolysis to trigger H2S and atorvastatin release. The responsive H2S release from ZnS can overcome the shortcomings of rapid H2S release from H2S donors in vivo. Furthermore, the ZnS hydrolysis-mediated H+ consumption in the microenvironment can reduce acidity to some extent. Results showed macrophage membranes (MM) coating reduced the phagocytosis of nanoparticles and increased the bioavailability. In vitro studies demonstrated that H2S release from MM/ZnS/ATV inhibited ROS-induced endothelial cell apoptosis and repaired the damaged endothelium. Moreover, atorvastatin released from MM/ZnS/ATV regulated lipid metabolism and reduced the blood lipid content. Both in vitro and in vivo studies confirmed MM/ZnS/ATV exhibited excellent therapeutic efficacy. Specifically, in vivo results showed that H2S combined with atorvastatin effectively reduced inflammatory infiltration, and promoted plaque regression and stabilization. Our study provides a promising strategy for atherosclerosis therapy.