Profiling Localized Immunomodulation and Drug Biodistribution within a Subcutaneous Vascularized Niche for Cell Transplantation

ABSTRACT Systemic immunosuppression remains essential for preventing allogeneic transplant rejection, but its chronic use causes substantial toxicity. Conceptually, local, site‐specific 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‐encapsulation 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‐Ig, anti‐lymphocyte serum, anti‐CD40L, anti‐CD2, and anti‐IL6. Sustained in situ exposure did not impair islet viability or function, and immunosuppressants were confined within the graft, with up to 100‐fold lower systemic concentrations. Individual agents produced distinct immune signatures, spanning lymphocyte depletion and shifts in T‐cell activation that can guide rational, mechanism‐informed combinations for allogeneic cell transplantation. These findings provide a comparative framework for evaluating localized immunosuppression with the potential to transform immunoprotection in cell therapy.