H2O2-responsive M2 macrophage membrane-camouflaged biomimetic nanosystems to dual-targeted delivery tanshinone IIA for enhanced anti-atherosclerosis

Atherosclerosis is a chronic inflammatory disease characterized by pathological vascular alterations, including endothelial cell dysfunction and apoptosis, macrophage infiltration, lipid deposition within the intima. Due to this complex pathophysiology, current therapeutic approaches lack effective systems for the precise delivery of antioxidant and anti-inflammatory agents to the affected sites. Herein we developed a reactive oxygen species (ROS)-responsive M2 macrophage membrane-camouflaged biomimetic drug delivery nanosystem (MM@TIIA-NPs) to dual-targeted delivery tanshinone IIA for enhanced anti-atherosclerosis. The dual-targeting capability arises from the combination of M2 macrophage membrane-mediated biological targeting, which promotes preferential accumulation at inflammatory atherosclerotic plaques while reducing reticuloendothelial system clearance, and H 2 O 2 -responsive microenvironmental targeting, which enables site-specific drug release within the oxidative plaque microenvironment. Following plaque accumulation, MM@TIIA-NPs would be internalized by the macrophages and vascular smooth muscle cells, leading to the reduced inflammatory responses and protection against apoptosis triggered by oxidative stress. Furthermore, these nanoparticles impeded foam cell development by limiting the absorption of oxidized low-density lipoproteins. In an established atherosclerotic zebrafish model, MM@TIIA-NPs demonstrated notable inhibition of lipid deposition, oxidative stress, and inflammatory responses, while restoring endothelial function. Similarly, the biocompatible MM@TIIA-NPs can preferentially accumulate in atherosclerotic lesions, resulting in significant reduction in necrotic core size, decreased macrophage infiltration and plaques stabilization in vivo studies conducted in ApoE −/− mice. In conclusion, MM@TIIA-NPs represent a promising therapeutic strategy for atherosclerosis management.