Abstract: In this study, licorice-derived vesicle-like particles (LVLPs) were used as carriers, and licochalcone-A (LCA), a signature active ingredient of the same source, was used as a model drug to construct a drug-loaded LVLP@LCA nanodelivery system, and to characterize and evaluate its in vitro properties and anti-inflammatory activity. Licochalcone-A (LCA), a signature active ingredient of traditional Chinese medicine from the same source, was used as a model drug to construct a drug-loaded exocyst-like nano-delivery system, LVLP@LCA, and its in vitro properties and anti-inflammatory activities were characterized and evaluated. The LVLP@LCA nanodelivery system was prepared by extracting the exocyst-like nanoparticles by gradient centrifugation and loading the anti-inflammatory drug LCA by ultrasonication. The LVLP@LCA nanoparticles were prepared with a particle size of about 160 nm and a tea saucershaped bilayer structure, with a high encapsulation rate and drug loading capacity. The in vitro results showed that LVLP@LCA further enhanced the ability of LCA to inhibit the proliferation of inflammatory cells and reduce the levels of ROS and NO in inflammatory cells. Meanwhile, ELISA and qRT-PCR results showed that LVLP@LCA significantly reduced the secretion and mRNA expression of IL-6, IL-1β, TNF-α, CCL5, CCL17 and other related inflammatory factors and chemokines. It was demonstrated by Western blot that LVLP@LCA reduced the expression of inflammation-inducing factor interleukin 6 (IL-6) through the JAK/STAT pathway, and then inhibited the activation of inflammatory response. The present study provides a theoretical basis for the comprehensive anti-inflammatory effect of LVLP@LCA and a new way of thinking for the application of Glycyrrhiza glabra as a traditional Chinese medicine against atopic dermatitis.