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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\u2010presenting 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\u2010inflammatory 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.<\/jats:p>","DOI":"10.1002\/smll.202307366","type":"journal-article","created":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T19:04:53Z","timestamp":1701457493000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Transdermal Microneedles Alleviated Rheumatoid Arthritis by Inducing Immune Tolerance via Skin\u2010Resident Antigen Presenting Cells"],"prefix":"10.1002","volume":"20","author":[{"given":"Yuanhao","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant\u2010Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School 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