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Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases. Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques. However, most of the nanocarriers are administered intravenously, which is inconvenient and may cause complications. Herein, we developed an oral lipid-polymer based nanoparticles (FA-LNPs) decorated with folic acid, which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages. Subsequently, naringenin (Nrg), one of the anti-inflammation drugs, was designed to be the oral nanomedicine (FA-LNPs/Nrg) for the first time via the encapsulation of FA-LNPs. FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy. After the atherosclerotic ApoE−/− mice were treated by FA-LNPs/Nrg via oral administration for three months, the aortic lesion area, plaque area, and necrotic core area of the aortic root were significantly decreased. Meanwhile, the lipid-related blood parameters recovered to normal levels. Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.
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