It is difficult to carry out early diagnosis and treatment of Multiple sclerosis (MS) because of the complex pathogenesis elicited by diversified autoantigens. Monocytes play important roles in the process of MS, especially as most of the amplified inflammatory monocytes cross the BBB to promote neuron injury and recruit more immune cells to infiltrate the central nervous system (CNS). Here, we propose monocytes as an effective immunotherapy target for MS. We used High-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) as a carrier to improve the bioavailability of curcumin. Curcumin-loaded HPPS (Cur-HPPS) were taken up specifically and efficiently by monocytes through the scavenger receptor class B type I (SR-B1) receptor. This delivery hindered inflammatory monocytes across the BBB in EAE mice, inhibited the proliferation of microglia, and restricted the infiltration of other effector immune cells, resulting in the reduction of EAE morbidity from 100% to 30%. It attributed to the immunomodulatory effect of Cur-HPPS on inflammatory monocytes, which inhibited NF-B activation and downregulated the expression of adhesion-and migration-related molecules. Meanwhile, infiltrated monocytes in the CNS of EAE mice characterize early inflammation. Therefore, targeted modulation of monocytes with HPPS carrying therapeutic and/or imaging agents offers a novel strategy for MS diagnosis and treatment. Copyright 2020 Elsevier Ltd. All rights reserved.