Kupffer Cells Degrade ¹⁴C-Labeled Few-Layer Graphene to ¹⁴CO₂ in Liver through Erythrophagocytosis

The distribution and clearance of graphene materials as drug delivery systems at organ and suborgan levels over the long term remain unclear. Here we compared the fate of 14C-labeled few-layer graphene with different lateral sizes in mice after one intravenous injection for up to 1 year and demonstrated that few-layer graphene mainly accumulated in the liver, and larger graphene can be degraded into 14CO2 by Kupffer cells. The mechanism involves the uptake of graphene by liver cells, larger graphene-induced membrane perturbation of red blood cells, and enhanced erythrophagocytosis by the Kupffer cells, resulting in the degradation of hemoglobin into hemes and a rise in iron concentrations in cells. The increased iron triggered a Fenton reaction to generate the hydroxyl radical, facilitating the degradation of larger graphene into 14CO2. Our findings propose a mechanism for the transformation of graphene that significantly contributes to our understanding of the hepatic fate of graphene in vivo.