Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD) caused by the aberrant attack of the immune system on its own joint tissues. Genetic and environmental factors are the main reasons of immune system impairment and high incidence of RA. Although there are medications on the market that lessen disease activity, there is no known cure for RA, and patients are at risk in varying degrees of systemic immunosuppression. By transporting (encapsulating or surface binding) RA-related self-antigens, nucleic acids, immunomodulators, or cytokines, tolerogenic nanoparticles—also known as immunomodulatory nano-preparations—have the potential to gently regulate local immune responses and ultimately induce antigen-specific immune tolerance. We review the recent advances in immunomodulatory nano-preparations for delivering self-antigen or self-antigen plus immunomodulator, simulating apoptotic cell avatars in vivo , acting as artificial antigen-presenting cells, and based on scaffolds and gels, to provide a reference for developing new immunotherapies for RA.
Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production. Aim: The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG2000 and Ca(OH)2. Methods: A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG2000 and Ca(OH)2 were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model. Results: Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN. Conclusion: NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.
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