GLP-1 Analogue-Loaded Glucose-Responsive Nanoparticles as Allies of Stem Cell Therapies for the Treatment of Type I Diabetes.

Abstract

Type 1 diabetes (T1D) is characterized by insufficient insulin secretion due to β-cell loss. Despite exogenous insulin administration being a lifesaving treatment, many patients still experience severe glycemic lability. For these patients, a β-cell replacement strategy through pancreas or pancreatic islet transplantation is the most physiological approach. However, donors' scarcity and the need for lifelong immunosuppressive therapy pose some challenges. This study proposes an innovative biomimetic pancreas, comprising β- and α-cells differentiated from human induced pluripotent stem cells (hiPSCs) embedded in a biofunctional matrix with glucose-responsive nanoparticles (NPs) encapsulating a glucagon-like peptide 1 (GLP-1) analogue, which aims to enhance the glucose responsiveness of differentiated β-cells. Herein, glucose-sensitive pH-responsive NPs encapsulating exenatide or semaglutide showed an average size of 145 nm, with 40% association efficiency for exenatide-loaded NPs and 55% for semaglutide-loaded NPs. Both peptides maintained their secondary structure after in vitro release and showed a similar effect on INS-1E cells' insulin secretion. hiPSCs were differentiated into β- and α-cells, and insulin-positive cells were obtained (82%), despite low glucose responsiveness, as well as glucagon-positive cells (17.5%). The transplantation of the developed system in diabetic mice showed promising outcomes since there was an increase in the survival rate of those animals. Moreover, diabetic mice transplanted with cells and exenatide showed a decrease in their glucose levels. Overall, the biomimetic pancreas developed in this work showed improvements in diabetic mice survival rate, paving the way for new cellular therapies for T1D that explore the synergy of nanomedicines and stem cell-based approaches.