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Transl. Med."],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:p>\n                    Tolerogenic dendritic cell (tolDC) vaccines are a promising antigen-specific therapy for multiple sclerosis (MS), yet their efficacy is limited by poor homing to secondary lymphoid organs and rapid loss of the tolerogenic phenotype in native inflamed lymph nodes. Here, we developed a 3D-printed tolerogenic artificial lymph node (tol-aLN) that creates a protected immune niche for durable tolerance induction. tolDCs were loaded onto a porous gelatin methacrylate scaffold engineered for sustained C-C motif chemokine ligand 21 (CCL21) release, recruiting na\u00efve CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and shielding tolDCs from an inflammatory lymph node. Geometric optimization of an orthogonal lattice scaffold enhanced spatially confined DC\u2013T cell interactions, promoting robust and stable induction of regulatory T cells (T\n                    <jats:sub>reg<\/jats:sub>\n                    cells). In experimental autoimmune encephalomyelitis (EAE), tol-aLN implantation attenuated disease even at advanced stages by inducing antigen-specific Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>reg<\/jats:sub>\n                    cells that trafficked to the spleen, lymph nodes, and central nervous system (CNS). Conditional T\n                    <jats:sub>reg<\/jats:sub>\n                    cell depletion abolished therapeutic efficacy, indicating that T\n                    <jats:sub>reg<\/jats:sub>\n                    cells are necessary mediators of tol-aLN\u2013induced protection. Long-term studies revealed sustained remission without impairing systemic immunity. In a myelin oligodendrocyte glycoprotein (amino acids 1 to 125) (MOG\n                    <jats:sub>1\u2013125<\/jats:sub>\n                    )\u2013induced EAE model, multivalent tol-aLN also efficiently suppressed inflammatory B cells and autoantibody production, reprogramming CNS B cells toward a regulatory state. Single-cell transcriptomics further revealed a global reduction in interferon-stimulated gene activity and restoration of homeostatic microglial phenotypes. Collectively, tol-aLN offers a scalable, antigen-specific platform for immune tolerance and CNS protection, with translational potential for MS and other autoimmune diseases.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aea7960","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:58:16Z","timestamp":1791395896000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Immunoregulatory artificial lymph nodes restore antigen-specific tolerance in advanced multiple sclerosis"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7117-8402","authenticated-orcid":true,"given":"Jingsen","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Minimally Invasive Interventional Radiology, Second Affiliated Hospital, School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3936-1685","authenticated-orcid":true,"given":"Ya","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou National Laboratory, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9387-9525","authenticated-orcid":true,"given":"Qi","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China."},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China."},{"name":"Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing, 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Liu Schematic overview of the synthesis and immunoregulatory mechanisms of tolerogenic artificial lymph nodes (tol-aLN). 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