Engineering Immunoregenerative Therapy via an Immunomodulatory Binary Pharmacology Hydrogel Depot for Prolonged Allograft Survival

ABSTRACT Immunosuppressive therapy following organ transplantation is essential for ensuring long‐term graft survival but leaves patients vulnerable to complications such as infection, malignancy, and severe side effects. 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‐restricted pharmacokinetics. A binary pharmacology‐loaded iGEL spontaneously formed upon subcutaneous implantation using a dual‐syringe system. Acting as a tissue‐adhesive depot, iGEL released key antirejection and tissue‐regenerative agents, enabling localized immunomodulation in response to rejection‐induced inflammation. In mouse major histocompatibility complex–mismatched allo‐transplant models, iGEL suppressed T‐cell activity while promoting vascular reconstruction and regulating local cytokine profiles to remodel immune‐regenerative 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‐term graft survival without systemic immunosuppression.