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

Abstract

ABSTRACT 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.