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Even though rare, 15 million Americans are collectively affected by autoimmune diseases, a number that continues to rise every year. Current treatment modalities primarily focus on alleviating symptoms rather than providing prevention or a cure. Tolerogenic dendritic cells (tolDCs) have gained popularity for autoimmune disease treatment as an alternative to traditional systemic immunosuppressive therapies due to their ability to restore immune homeostasis. However, clinical translation of tolDC therapies faces significant hurdles once injected into the body due to suboptimal delivery routes, systemic distribution throughout the body, faster clearance rate, phenotypic instability, and inefficient homing. So, the big question here is: How can we retrain dendritic cells to restore the immune balance while overcoming these challenges? Engineered biomaterials such as nanoparticles, microparticles, hydrogels, and polymer scaffolds offer innovative solutions by enabling targeted delivery of ex\u00a0vivo\u2010generated tolDCs or in\u00a0situ reprogramming of endogenous dendritic cells (DCs) by delivering drugs and other bioactive agents at strategic locations. These platforms provide tunable release kinetics, enhanced targeting specificity, improved safety profiles, and high potency, highlighting their importance as a promising alternative to conventional administration methods. Biomaterials can modulate immune responses from inflammatory immune activation to immune tolerance, which is essential for long\u2010term disease management. This review highlights recent advances in biomaterial\u2010based delivery systems for DC delivery and their potential to redefine therapeutic strategies for autoimmune diseases.<\/jats:p>","DOI":"10.1002\/jbm.a.70107","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T06:09:09Z","timestamp":1782194949000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomaterial\u2010Focused Strategies Targeting Dendritic Cells for Autoimmune Disease Treatment"],"prefix":"10.1002","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5709-5345","authenticated-orcid":false,"given":"Aiswarya","family":"Venkata Suresh Kumar","sequence":"first","affiliation":[{"name":"Wallace H. 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