Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies

Abstract

Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.

Keywords: Immune tolerance; Inflammation resolution; Liposome; Micelle; Nanomedicines; Rheumatoid arthritis; Stimulus-responsive delivery systems; Targeted drug delivery.

Graphical abstract

Figure 1

The comparison of physiological microenvironment between normal synovium and inflamed sites. Compared with normal synovial tissues, massive inflammatory cells are recruited to inflamed joints. Afterwards, rapid proliferation and activation of cells involved in inflammation lead to the formation of pannus and the thickening of the synovial lining. Antigen-presenting cells (APCs) including DCs, activated B cells and macrophages present antigens to T cells, leading to the activation of autoreactive T cells. Other than antigen presentation, B cells would also secrete autoantibodies such as ACPA and RF, which can attack our own tissues. On the other hand, large number of inflammatory cytokines (TNF-α, IL-6 and IL-1) and invasive proteases would be produced, mediating the expansion of inflammatory network and the destruction of cartilage and bone tissue. FLS, fibroblast-like synoviocyte; DC, dendritic cell; VEC, vascular endothelial cells; MMPs, matrix metalloproteinase; Autoantibodies including rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPAs); Inflammatory cytokines including TNF-α, IL-1β, IL-6, etc.

Figure 2

Schematic illustration of active targeting delivery strategies.

Figure 3

The newly emerged promising therapeutic approaches for RA treatment. (a) Endogenous pro-resolving mediators initiate resolution function by acting on specific cell types, including promoting macrophages repolarization from pro-inflammatory M1 type to anti-inflammatory M2 type, facilitating neutrophils apoptosis and play a key role in chondroprotection and osteoclastgenesis inhibition. (b) Cells involved in inflammation development would undergo a metabolic reprogramming, displaying a highly increased metabolic demand. Increased anabolic metabolism would promote inflammation and motivate immune response. Therefore, facilitating the balance of cell metabolism would be a possible therapeutic intervention option. (c) Induction of specific immune tolerance during the interaction between DCs and T cells would produce increased level of T_reg and decrease the level of autoreactive immune cells, which might provide a long-term, sustained disease remission.