Abstract: OBJECTIVE To construct receptor-mediated and lactoferrin-modified liposomes of Codonopsis pilosula polysaccharide(Lf-CPPS-LCL) by selecting lactoferrin(Lf) as brain targeting ligand, and to investigate its ability to cross blood-brain barrier and anti-inflammatory effect in vitro. METHODS CPPS-Lips was prepared by reverse evaporation method. The optimal prescription was screened by the Box-Behken design-response surface methodology using the encapsulation rate as the index. The amino group of Lf was covalently combined with DSPE-PEG2000-COOH on the surface of the liposome membrane to obtain Lf-CPPS-LCL. Then its morphology, particle size, potential and release degree in vitro were investigated. Established an in vitro blood-brain barrier model by co culturing human umbilical vein endothelial cells and rat glioma C6 cells to investigate the permeability of Lf-CPPS-LCL. Lipopolysaccharide was used to induce inflammation model in BV2 cells. And the BV2 cells were treated with CPPS, CPPS-Lips, and Lf-CPPS-LCL. The levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1β and IL-6 was measured by ELISA. Western blotting was applied to determine the expression levels of Toll-like receptor 4(TLR4), myeloid differentiation factor(MyD88) and nuclear factor-κB(NF-κB) in BV2 cells. RESULTS The optimal prescription was determined as follows:The ratio of lipid to drug was 31:1, the ratio of soybean phospholipid to cholesterol was 28:5, sonication time was 25 min, and molar content of DSPE-PEG2000 was 5%. The particle size of Lf-CPPS-LCL was (197.5±0.6)nm, the PDI was (0.2±0.02), and the Zeta potential was (-18.8±1.1)mV. Compared with the raw material drug, Lf-CPPS-LCL was released more slowly and smoothly in vitro. Compared with unmodified liposomes, Lf-modified liposomes had better permeability to the blood-brain barrier model. Compared with the model group, Lf-CPPS-LCL significantly reduced the release of inflammatory factors TNF-α, IL-1β and IL-6 and down-regulated the protein expression of TLR4, NF-κB and MyD88 in BV2 cells(P<0.05 or P<0.01). CONCLUSION Lf-CPPS-LCL has a rounded morphology, with uniform particle size distribution, good sustained release and blood-brain barrier model permeability. Lf-CPPS-LCL could effectively inhibit LPS-induced inflammatory response in BV2 cells, and its mechanism of action may be related to the down-regulation of TLR4 and the protein expression of MyD88 and NF-κB on its downstream.