{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:04:32Z","timestamp":1789362272986,"version":"build-2803163510"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Tolerogenic dendritic cells (tolDCs) are a promising cell therapy platform for restoring immune tolerance, but their clinical efficacy is limited by poor phenotypic stability and short\n                    <jats:italic>in vivo<\/jats:italic>\n                    persistence following transfer. Here, we developed biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles co-loaded with ovalbumin (OVA) and a combinatorial Push\/Pull Immunomodulation (PPI) formulation consisting of the TLR7\/8 agonist resiquimod (R848) and the JAK2 inhibitor CEP-33779. We hypothesized that sustained intracellular release of immunomodulators from phagocytosed microparticles would stabilize tolDC phenotype and enhance antigen-specific regulatory T cell (Treg) responses. PPI microparticles (PPI MPs) demonstrated sustained cargo release over 30 days, with the most pronounced pH sensitivity observed for CEP-33779, and were efficiently internalized by murine bone marrow-derived dendritic cells (BMDCs) and human monocyte-derived dendritic cells. BMDCs loaded with PPI MPs exhibited prolonged viability, increased PD-L1 and IL-10 expression, and resistance to inflammatory reprogramming following lipopolysaccharide challenge compared to dexamethasone-loaded microparticles or soluble drug controls. Administration of PPI MPs during BMDC differentiation further enhanced tolerogenic programming, producing marked increases in PD-L1 and IL-10 while suppressing TNF\u03b1 secretion. Following adoptive transfer\n                    <jats:italic>in vivo<\/jats:italic>\n                    , PPI MP-treated DCs demonstrated prolonged persistence and accumulation in draining lymph nodes for up to 7 days. Finally, PPI MP-treated DCs induced robust antigen-specific Foxp3+ regulatory T cell responses in OVA-sensitized mice and suppressed antigen recall responses ex vivo. Together, these findings demonstrate that sustained intracellular combinatorial immunomodulation can generate a durable and functionally stable tolDC phenotype with enhanced antigen-specific tolerogenic activity, supporting this platform as a potential strategy for autoimmune therapies.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1897468","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:33:06Z","timestamp":1789360386000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Sustained microparticle-mediated intracellular immunomodulation enhances tolerogenic dendritic cell stability and antigen-specific Treg induction"],"prefix":"10.3389","volume":"17","author":[{"given":"Sihan","family":"Jia","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering, Drexel University","place":["Philadelphia, PA, United 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