Efficiently Inhibiting Systemic Inflammatory Cascades by Fullerenes for Retarding HFD‐Fueled Atherosclerosis

Abstract Atherosclerosis accounts for major mortality of cardiac‐cerebral vascular diseases worldwide. Pathologically, persistent inflammation dominates the progression of atherosclerosis, which can be accelerated by a high‐fat diet (HFD), possibly through triggering local intestinal oxidative stress and ensuing gut barrier dysfunction. Current pharmacotherapy has been disappointing, ascribed to limited therapeutic efficacy and undesirable side effects. Hence it is compelling to explore novel efficient anti‐atherosclerotic drugs with minimal toxicity. Herein, two fullerene‐based therapies with exceptional antioxidant capacity, in the form of water‐soluble injectable fullerene nanoparticles (IFNPs) and oral fullerene tablets (OFTs), are demonstrated to retard HFD‐fueled atherosclerosis in ApoE −/‐ mice with favorable biosafety. Especially, OFTs afford robust anti‐atherosclerotic therapeutic even against advanced plaques, besides stabilizing plaques with less lipid deposition and improved collagen expression. Specifically, it is identified that OFTs can ameliorate HFD‐induced dysregulated intestinal redox homeostasis and restore gut barrier integrity, thereby restraining the translocation of luminal lipopolysaccharide (LPS) into the bloodstream. Furthermore, significantly reduced circulating LPS after OFTs treatment contributes to down‐regulated LPS/TLR4/NF‐ κ B signaling in aortic focal, which further mitigates local inflammation and disease development. Overall, this study confirms the universal anti‐atherosclerotic effect of fullerenes and provides a novel therapeutic mechanism via modulating intestinal barrier to attenuate atherosclerosis.