Remodeling macrophage efferocytosis and phenotype via targeted nanoimmunotherapy for atherosclerosis

Macrophages within advanced atherosclerotic lesions typically exhibit impaired efferocytosis and tend to adopt a pro-inflammatory M1-like phenotype, leading to the progression of atherosclerosis. Despite this challenge, the development of biocompatible nanotherapeutics capable of effectively remodeling macrophage efferocytosis and phenotype remains elusive. Here, we developed engineered targeted-peptide-modified nanocarriers (PP) and demonstrated their potential to restore macrophage efferocytosis while promoting re-polarization towards an anti-inflammatory M2-like phenotype. Furthermore, PP efficiently facilitated the delivery of an inflammation-resolving-drug to lesional macrophages within advanced atherosclerotic lesions. This combination approach substantially enhanced the anti-atherosclerotic efficacy of PP-based nanomedicine, effectively ameliorating atherosclerosis progression. In advanced plaque-bearing ApoE ^-/- mice, PP nanomedcine efficiently accumulated in atherosclerotic plaques, notably restoring macrophage efferocytosis, promoting anti-inflammatory M2-like macrophage polarization, and leading to reduced plaque areas and enhanced plaque stability. This study not only underscores the new pleiotropic effects of PP to restore macrophage efferocytosis and modulate macrophage phenotype, but also highlights the promising potential of PP for the treatment of atherosclerosis and diseases associated with macrophage dysfunction.