CD40L is considered as an important target for the treatment of autoimmune diseases. There have been many efforts devoted to the development of antibodies and other molecules to disrupt CD40/CD40L interaction for therapeutic benefits. In this study, we designed a CD40L specific peptide ligand — A25 based on CD40L crystal structure and molecular docking studies. Its binding affinity and specificity to CD40L were confirmed by Surface Plasmon Resonance (SPR) measurements. The peptide A25 was then conjugated on the surface of liposomes and shown to be able to mediate specific liposomal drug delivery to CD40L+ cells. Loaded with the cytostatic drug methotrexate (MTX), the A25 modified liposome could significantly reduce the CD40L+ cell ratios in the experimental autoimmune encephalomyelitis (EAE) mice, resulting in great improvement in clinical scores. Since CD40L+ cells are involved in the pathological development of many auto-immune diseases, A25 conjugated drug targeting systems may be useful for developing therapies that are more efficacies and with less side effects.