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Atherosclerosis, characterized by the accumulation of inflammatory cells at localised inflammatory sites with a high concentration of reactive oxygen species (ROS), is a leading cause of cardiovascular morbidity and mortality worldwide. There is a paucity of studies that effectively coordinate the targeting of inflammatory microenvironment and the controlled release of biomimetic carriers. Here, in view of the oxidative stress and inflammatory characteristics observed in the plaque microenvironment of atherosclerosis lesions, we propose an anti-inflammatory M2 macrophage membrane-derived nanovesicles co-fused with lipids containing ROS-sensitive thioketal (TK) linker and loaded with rapamycin (Rapa) to form a biomimetic hybrid system (Rapa@TLNVs). Benefiting from the inflammatory tendency of vesicles and ROS response of TK, Rapa@TLNVs can be delivered to plaque lesions and responsively release Rapa to synergistically help suppressing inflammation. Additionally, Rapa@TLNVs can reduce foam cells formation and the proliferation of macrophages. Following the administration of Rapa@TLNVs to ApoE−/− mice, a series of effects have been observed, including reductions in the inflammatory response, lipid deposition and increased plaque stability. Consequently, this work exploits the characteristics of the atherosclerosis plaque microenvironment to provide a promising strategy for combating atherosclerosis. This may further enrich the application experience of biomimetic hybrid nanovesicle platforms in atherosclerosis therapy. [Display omitted] • The biomimetic hybrid vesicles can combine the ROS responsiveness of TK and the inflammatory tropism conferred by M2 NVs. • TLNVs can target aortic plaques and eliminate ROS, cooperating with Rapa to regulate inflammation. • Rapa@TLNVs can effectively inhibit macrophage proliferation and inflammation, reduce foam cells, and treat AS. [ABSTRACT FROM AUTHOR]