Graphene Oxide Causes Disordered Zonation due to Differential Intralobular Localization in the Liver.

Liver is the primary organ to sequester nanodrugs, representing a substantial hurdle for drug delivery and raising toxicity concerns. However, the mechanistic details underlying the liver sequestration and effects on liver are still elusive. The difficulty in studying the liver lies in its complexity, which is structured with stringently organized anatomical units called lobules. Graphene oxide (GO) have attracted attentions for their applications in biomedicine, especially as nanocarrier, however, its sequestration and effects in the liver, the major enrichment and metabolic organ, are less understood. Herein, we unveiled the differential distribution of GO in lobules in the liver, with higher amount surrounding portal triad (PT) zones than the central vein (CV) zones. Strikingly, liver zonation patterns also changed, as reflected by changes in vital zonated genes involved in hepatocyte integrity and metabolism, leading to compromised hepatic functions. RNA-Seq and DNA methylation sequencing analyses unraveled that GO-induced changes in liver functional zonation could be ascribed to dysregulation of key signaling pathways governing liver zonation at not only mRNA transcriptions but also DNA methylation imprinting patterns, partially through TET-dependent signaling. Together, this study unearths the differential GO distribution pattern in liver lobules, and pinpoints the genetic and epigenetic mechanisms in GO-induced liver zonation alterations.