Black phosphorus nanoplatform coated with platelet membrane improves inhibition of atherosclerosis progression through macrophage targeting and efferocytosis.

Plaque rupture in atherosclerosis (AS) is a major cause of acute cardiovascular events. Macrophage-induced inflammatory responses and accumulation of excess reactive oxygen species (ROS) primarily induce unstable plaques. Therefore, targeting ROS clearance and functional modulation of macrophages are clinically crucial for improving plaque stability and inhibiting AS progression. Here, we constructed a bionic nano-delivery platform, PBP@siR@PM, using platelet membranes (PM) coated with black phosphorus nanosheets (BPNSs) to target macrophages in atherosclerotic plaques. Meanwhile, PM-coated BPNSs (PBP@siR@PM) were used to deliver small interfering RNA silencing Ca/calmodulin-dependent protein kinase γ (CaMKIIγ) into macrophages. Furthermore, macrophage efferocytosis was restored by inhibiting CaMKIIγ and increasing the expression of MerTK, a cytosolic receptor, thus promoting the clearance of apoptotic cells from plaques. This study demonstrated that intraplaque macrophage-targeted therapy using the bionic nano-delivery platform PBP@siR@PM effectively removed excess ROS from macrophages, promoted efferocytosis, cleared apoptotic cells in plaques, improved plaque stability, and largely inhibited AS progression in ApoE mice after high fat diet. In summary, this study proposes a therapeutic strategy for AS and highlights the outstanding therapeutic potential of biomimetic nanomaterials in this type of chronic inflammatory disease. STATEMENT OF SIGNIFICANCE: Rupture of atherosclerotic unstable plaques is a major cause of acute cardiovascular events. Macrophage-induced chronic inflammation and oxidative stress due to overloaded ROS are major contributors to plaque rupture. In this study, we focused on the improvement of macrophage efferocytosis within the plaque for the effective treatment of atherosclerosis. A bionic nano-delivery platform was constructed using platelet membranes (PM) coated black phosphorus nanosheets (BPNSs) to target macrophages in atherosclerotic plaques. In conclusion, intraplaque macrophage-targeted therapy based on the bionic nano-delivery platform PBP@siR@PM effectively scavenges overloaded ROS in macrophages, promotes efferocytosis, removes apoptotic cells from plaques, and improves plaque stability, which significantly inhibits the progression of atherosclerosis in ApoE mice after a high-fat diet.