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Immunosuppressants currently in use are typically hydrophobic with low oral bioavailability and must be taken indefinitely to maintain immune tolerance. Furthermore, these drugs lack tissue repair capacity, which limits their effectiveness in transplantation. To address this clinical gap, an immunomodulatory hydrogel (iGEL) was developed, integrating prodrug engineering with inflammation\u2010restricted pharmacokinetics. A binary pharmacology\u2010loaded iGEL spontaneously formed upon subcutaneous implantation using a dual\u2010syringe system. Acting as a tissue\u2010adhesive depot, iGEL released key antirejection and tissue\u2010regenerative agents, enabling localized immunomodulation in response to rejection\u2010induced inflammation. In mouse major histocompatibility complex\u2013mismatched allo\u2010transplant models, iGEL suppressed T\u2010cell activity while promoting vascular reconstruction and regulating local cytokine profiles to remodel immune\u2010regenerative dynamics. For both immunocompetent and metabolically compromised hosts, iGEL effectively restored the functionality of skin allografts and markedly extended survival. The study introduces a locally syringeable and adaptive hydrogel depot that harnesses pathological cues to mediate complementary immune regulation and tissue repair, ensuring long\u2010term graft survival without systemic immunosuppression.<\/jats:p>","DOI":"10.1002\/advs.202520994","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:27:31Z","timestamp":1783420051000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering Immunoregenerative Therapy via an Immunomodulatory Binary Pharmacology Hydrogel Depot for Prolonged Allograft Survival"],"prefix":"10.1002","volume":"13","author":[{"given":"Ning","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Hepatobiliary and Pancreatic Surgery Department of Surgery The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"NHC Key Laboratory of Combined Multi\u2010Organ Transplantation Key Laboratory of Organ Transplantation Zhejiang Province. 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