Microcrystalline-Infused Peptide Hydrogel Enables Sustained Tacrolimus Delivery to Prolong Survival and Prevent Rejection in Kidney Transplantation.

Tacrolimus (TAC) is essential in post-kidney transplantation immunosuppressive therapy but is hindered by its narrow therapeutic window and patient long-term adherence challenges, leading to severe side effects in recipients. To address this, we developed an injectable self-assembling peptide hydrogel that encapsulates TAC within a microcrystalline phase via a novel multiphase assembly strategy. This hydrogel enables sustained TAC release, maintaining therapeutic blood concentrations (5-15 ng/mL) for seven days post-injection. In a vascularized composite allotransplant model, TAC-loaded hydrogel preserves skin integrity on day 7 with vessel sutures, highlighting its potential for tissue preservation. In a life-sustaining kidney transplantation model, rats receiving a single injection of TAC-loaded hydrogel exhibited significantly improved survival (∼68 days) compared to the oral administration group (∼21 days). Histopathological and blood analysis confirmed minimal inflammation and intact tissue architecture in hydrogel-treated grafts, alongside no systemic toxicity in major organs. These findings highlight multiphase assembly as a novel, effective strategy for controlled TAC release, offering a promising approach to improve patient outcomes in organ transplantation.