Transdermal Microneedles Alleviated Rheumatoid Arthritis by Inducing Immune Tolerance via Skin-Resident Antigen Presenting Cells

Restoring immune tolerance is the ultimate goal for rheumatoid arthritis (RA) treatment. The most reported oral or intravenous injection routes for the immunization of autoantigens cause gastrointestinal side effects, low patient compliance, and unsatisfied immune tolerance induction. Herein, the use of a transdermal microneedle patch is for the first time investigated to codeliver CII peptide autoantigen and rapamycin for reversing immune disorders of RA. The immunized microneedles efficiently recruit antigen-presenting cells particularly Langerhans cells, and induce tolerogenic dendritic cells at the administration skin site. The tolerogenic dendritic cells further homing to lymph nodes to activate systemic Treg cell differentiation, which upregulates the expression of anti-inflammatory mediators while inhibiting the polarization of Th1/2 and Th17 T cell phenotypes and the expression of inflammatory profiles. As a result, the optimized microneedles nearly completely eliminate RA symptoms and inflammatory infiltrations. Furthermore, it is demonstrated that a low dose of rapamycin is crucial for the successful induction of immune tolerance. The results indicate that a rationally designed microneedle patch is a promising strategy for immune balance restoration with increased immune tolerance induction efficiency and patient compliance. The autoantigen and rapamycin coloaded polymeric microneedle patch is promising for inducing immune tolerance for rheumatoid arthritis (RA) treatment. The fabricated microneedles can effectively target to antigen-presenting cells (APCs) in the skin, and restore immune balance in RA by suppressing proinflammation cytokines, antibodies, and by upregulating anti-inflammation signals including Treg cells and anti-inflammation cytokines, which as a result nearly completely eliminated RA symptoms.image

Automated summary

This study investigated the use of a transdermal microneedle patch to deliver CII peptide autoantigen and rapamycin for the treatment of rheumatoid arthritis. The microneedles effectively recruited antigen-presenting cells and induced tolerogenic dendritic cells, leading to the activation of Treg cells and the suppression of proinflammatory cytokines, ultimately eliminating RA symptoms. Low dose of rapamycin was found to be crucial for successful immune tolerance induction. This rationally designed microneedle patch shows promise for immune balance restoration and improved patient compliance.