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The development of xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph\u2010node (LN)\u2010targeted drug delivery can realize LN\u2010specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long\u2010term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C\u2010C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO<jats:sub>3<\/jats:sub>\/CaP\/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (T<jats:sub>regs<\/jats:sub>) and decreasing the proportion of effector T cells (T<jats:sub>effs<\/jats:sub>) in dLNs after heart transplantation, the LN\u2010targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long\u2010term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.<\/jats:p>","DOI":"10.1002\/adma.202207227","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T06:10:20Z","timestamp":1667196620000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Lymph\u2010Node\u2010Targeted Drug Delivery for Effective Immunomodulation to Prolong the Long\u2010Term Survival After Heart Transplantation"],"prefix":"10.1002","volume":"35","author":[{"given":"Yan\u2010Jia","family":"Che","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery Renmin Hospital of Wuhan University  Wuhan 430060 P. R. 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