Abstract
Islet transplantation is a promising therapy for diabetes, yet the limited survival and functionality of transplanted islet grafts hinder optimal outcomes. Glucagon-like peptide-1 (GLP-1), an endogenous hormone, has shown potential to enhance islet survival and function; however, its systemic administration can result in poor localization and undesirable side effects. To address these challenges, we developed a novel peptide-based nanofiber hydrogel incorporating GLP-1 functionality for localized delivery. By conjugating the FFG tripeptide (a self-assembling motif derived from phenylalanine-phenylalanine-glycine) to the C-terminus of native GLP-1, we engineered GLP-1-FFG, a self-assembling peptide that forms a robust nanofiber structure resistant to enzymatic degradation. When GLP-1-FFG co-assembles with the biotin-DFYIGSRGD peptide (referred to as SupraGel), a self-assembling supramolecular polypeptide hydrogel we previously identified containing motifs derived from extracellular matrix components, the resulting hydrogel (SupraGel + GLP-1-FFG) creates a stable nanofibrous network with excellent rheological properties. In vitro, this nanofiber hydrogel significantly improves islet function and survival. Bulk RNA sequencing results demonstrate that the hydrogel suppresses the expression of hypoxia-related genes, downregulates pro-inflammatory genes, and upregulates genes associated with islet function. Further analysis reveals that these effects are related to the activation of the AKT signaling pathway. In a syngeneic mouse islet transplantation model, the localized application of SupraGel + GLP-1-FFG at the renal subcapsular islet transplant site significantly enhanced the efficacy of marginal-dose islet transplantation, as shown by improved glycemic control, faster and higher rates of diabetes reversal, better glucose tolerance, and greater islet graft survival in diabetic recipient mice. This innovative nanotechnology-based hydrogel offers a promising strategy for enhancing the efficacy of islet grafts in transplantation therapy.