GO‐PEG Represses the Progression of Liver Inflammation via Regulating the M1/M2 Polarization of Kupffer Cells

Abstract As a highly promising nanomaterial, exploring the impact of the liver, a vital organ, stands out as a crucial focus in the examination of its biological effects. Kupffer cells (KCs) are one of the first immune cells to contact with exotic‐substances in liver. Therefore, this study investigates the immunomodulatory effects and mechanisms of polyethylene glycol‐modified graphene oxide (GO‐PEG) on KCs. Initial RNA‐seq and KEGG pathway analyses reveal the inhibition of the TOLL‐like receptor, TNF‐α and NOD‐like receptor pathways in continually stimulated KCs exposed to GO‐PEG. Subsequent biological experiments validate that a 48‐hour exposure to GO‐PEG alleviates LPS‐induced KCs immune activation, characterized by a shift in polarization from M1 to M2. The underlying mechanism involves the absorption of double‐stranded RNA/single‐stranded RNA, inhibiting the activation of TLR3 and TLR7 in KCs. Employing a Kupffer/AML12 cell co‐culture model and animal studies, it is observed that GO‐PEG indirectly inhibit oxidative stress, mitochondrial dysfunction, and apoptosis in AML12 cells, partially mitigating systemic inflammation and preserving liver tissue/function. This effect is attributed to the paracrine interaction between KCs and hepatocytes. These findings suggest a meaningful and effective strategy for treating liver inflammation, particularly when combined with anti‐inflammatory drugs.