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Conceptually, local, site\u2010specific immunomodulation offers a promising alternative, yet comparative mechanistic insight into how immunosuppressants behave when delivered directly to the graft is lacking. Here, we leveraged the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, a subcutaneous, vascularized cell\u2010encapsulation platform, as a spatially defined and reproducible model to study local immunomodulation in allogeneic islet transplantation. We systematically profiled the safety, local and systemic immunomodulatory effects, pharmacokinetics, and longitudinal biodistribution of five clinically relevant agents delivered locally at the graft site: CTLA4\u2010Ig, anti\u2010lymphocyte serum, anti\u2010CD40L, anti\u2010CD2, and anti\u2010IL6. Sustained in situ exposure did not impair islet viability or function, and immunosuppressants were confined within the graft, with up to 100\u2010fold lower systemic concentrations. Individual agents produced distinct immune signatures, spanning lymphocyte depletion and shifts in T\u2010cell activation that can guide rational, mechanism\u2010informed combinations for allogeneic cell transplantation. These findings provide a comparative framework for evaluating localized immunosuppression with the potential to transform immunoprotection in cell therapy.<\/jats:p>","DOI":"10.1002\/advs.202520914","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T04:27:54Z","timestamp":1773030474000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Profiling Localized Immunomodulation and Drug Biodistribution within a Subcutaneous Vascularized Niche for Cell Transplantation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0523-1970","authenticated-orcid":false,"given":"Jocelyn Nikita","family":"Campa\u2010Carranza","sequence":"first","affiliation":[{"name":"Center for BioNanoengineering Houston Methodist Research Institute  Houston Texas USA"},{"name":"School of Medicine and Health Sciences Tecnologico de Monterrey  Monterrey Nuevo Le\u00f3n 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