Devouring Atherosclerotic Plaques: The Engineered Nanorobot Rousing Macrophage Efferocytosis by a Two‐Pronged Strategy

Abstract Investigating the potential of macrophage efferocytosis has led to a growing interest in exploiting macrophage in immunotherapy. Macrophage‐specific nano‐medicines are currently being developed to stimulate the phagocytic clearance of apoptotic debris in atherosclerosis; however, these unnatural nanoparticles exhibit poor biocompatibility and limited efferocytosis activation ability. Here a pro‐efferocytosis biomimetic nanorobot UM‐EV Lipo is developed based on nano‐motor and extracellular vesicles (EVs) hybridized with plaque double‐targeted liposomes. An elegant procedure with only 4 steps is integrated to prepare and purify these hybrid nanovesicles. It is first demonstrated that the EVs derived from bone marrow macrophages stimulated with IL‐4 can promote the transformation of M0 and M1 macrophages into M2, an efferocytosis phenotype. Furthermore, the EVs hybridized with SHP‐1 siRNA‐liposomes blocked the “don't eat me” signal from apoptotic debris by intervening CD47‐SIRPα‐SHP‐1 axis. This two‐pronged strategy of resetting phenotype and blocking checkpoints furthest activates macrophage efferocytosis. Importantly, the urease motor increased the swimming speed of nanovesicles in the blood by 12.4 times, making it easier for them to penetrate the endothelial barrier. The UM‐EV Lipo accumulated within the atherosclerotic plaque, reactivate lesioned efferocytosis and reduce the plaque area in the carotid and coronary, which demonstrates the potential of a two‐pronged strategy to prevent atherosclerotic cardiovascular disease.