T cell/Macrophage Dual-Targeting Biomimetic Triptolide Self-Assembly Nanodrugs For Rheumatoid Arthritis Therapy by Inflammatory Microenvironment Remodeling

Rheumatoid arthritis (RA) is an autoimmune disease causing severe joint damage, disability and decreased quality of life. Pathologically, numerous blood-derived cells infiltrating in synovium and cytokine secret necessitating formation of new blood vessels to generate pannus together form an inflammatory microenvironment. Triptolide with immunosuppressive activities is a potential drug to treat RA. However, it is still lack of an effective targeting system to deliver triptolide to RA site safely. Herein an inflammatory microenvironment targeting and remodeling nanoplatform is developed to achieve significantly effective RA treatment. In this system we synthesized a self-assembling triptolide nanoparticles (TPNs) mediated by dipeptide diphenylalanine which is the simplest self-assembly building block, then TPNs were entrapped by mannose-modified erythrocyte membranes to form engineering manRTPNs. For targeting, the immunological molecule of erythrocytes was firstly introduced to target T cells by ligand binding of LFA-3/LFA-2, and the coated mannose modified erythrocyte membrane also conferred the capacity of targeting to macrophages by mannose and its receptor CD206; for remodeling inflammatory microenvironment, TPNs could selectively exert its suppressive effects on different cells of RA including lymphocytes and synovial fibroblasts. In collagen
induced arthritis mice, manRTPNs showed excellent targeting effect and prolonged accumulation at inflamed joint. After manRTPNs treatment, swollen paws of CIA considerably shrunk to normal, boss loss even recovered healthy level and cartilage preserved at synovium cavity, because of systemically conventional cytokine reduction and expression shift of core genes in networks of RA microenvironment. Therefore, this well-defined manRTPNs might be a well promising systematic therapeutic agent for RA.