Bilirubin Nanomedicine Alleviates Inflammation and Angiogenesis in a Rosacea Mouse Model

Abstract Rosacea is a common chronic inflammatory facial disorder. Reactive oxygen species (ROS) have a key role in the pathogenesis of rosacea. In this study, the antioxidant and anti‐inflammatory effects of bilirubin‐based nanoparticles (BRNPs) are investigated in the LL‐37‐induced rosacea‐like mouse model. Effects of BRNPs on rosacea‐like skin inflammation and ROS level of the skin are determined using histological analysis. The expression of genes encoding rosacea‐associated cytokines and chemokines is assessed and the molecular mechanisms of BRNPs against rosacea are investigated using RNA sequencing (RNAseq) analysis. This study reveals that BRNPs significantly alleviate LL‐37‐induced inflammatory manifestation in the rosacea mouse model and reduce the expression of proinflammatory cytokines (interleukin [IL]‐1β, IL‐6, and tumor necrosis factor [TNF]‐α) and chemokines (C‐X‐C motif chemokine ligand 8 [CXCL8] and CXCL10). Moreover, BRNPs preferentially localize at the inflammatory skin lesion, decrease the level of ROS in the skin, and ameliorate the vascular endothelial growth factor expression and vascular changes in the skin induced by LL‐37. Furthermore, these findings provide a mechanism for the efficacy of BRNPs in this experimental model and support BRNPs as a potential therapeutic option for rosacea and other related inflammatory skin disorders.