Engineered macrophages containing RvE1 enable treatment of atherosclerosis by immune training and phenotypic modulation of macrophages

Abstract Currently, the management of atherosclerosis is primarily limited to pharmacological interventions and invasive procedures, prompting ongoing efforts among researchers to transform therapeutic strategies. Macrophages, as key immune cells involved in the pathogenesis of atherosclerosis, play critical roles in cholesterol transport and efflux, modulation of vascular inflammation, clearance of apoptotic cells via phagocytosis, and regulation of plaque stability through the secretion of matrix metalloproteinases or protease inhibitors. In contrast to conventional nanoparticle-based targeting approaches, we have developed a novel layer-by-layer self-assembled, micron-sized, disc-shaped platform known as "Cellular Backpacks (BPs)," incorporating Resolvin E1, a specialized pro-resolving mediator. These BPs can stably adhere to macrophages and induce immunomodulatory reprogramming. We have successfully engineered a macrophage-BP complex (BPs-Mø) with enhanced capabilities for targeted drug delivery, functional and phenotypic modulation of macrophages, cholesterol transport and efflux, and regulation of plaque stability. Our results demonstrate that BPs-Mø effectively suppress the progression of atherosclerosis and promote plaque regression. Graphical Abstract