Pancreatic islet transplantation has been researched as a therapeutic approach for Type 1 diabetes mellitus (T1D) patients due to its ability to control blood glucose levels dynamically and precisely. However, there are several obstacles to this treatment, including poor engraftment of islets and long-term administration of immunosuppressive agents that can have adverse effects. The host immune response, in particular the release of the protein high-mobility group box 1 (HMGB1) from implanted islet cells, is one of the main problems. HMGB1 is a crucial role in the response to tissue damage as an inflammatory mediator and a damage-associated molecular pattern (DAMP) molecule. When islets are damaged, they secrete HMGB1, which binds to the Toll-Like Receptors (TLR) and the Receptor for Advanced Glycation End Products (RAGE) in immune cells and potently stimulates immune responses. This immune response can lead to poor outcomes in islet cell therapy, therefore, neutralizing the activity of HMGB1 provide a successful outcomes of islet cell therapy.

This study presents a novel surface camouflage that can be applied to living pancreatic islets isolated from rats. Glycyrrhizin (GL), a well-known HMGB1 inhibitor, binds directly to the HMGB1, and the glycol chitosan-GL conjugate, which has HMGB1 binding affinity and scavenges Reactive Oxygen Species (ROS), ultimately suppresses the immune response. The glycol chitosan-GL on the islet surface is camouflaged by the polyethylene glycol (PEG), which improves the hydrodynamic volume and prevents immune cell assaults (Glycol chitosan-GL @islet).

The binding capacity to HMGB1 of glycol chitosan-GL was confirmed employing SPR technique, and with repeated PEGylation, the amount of glycol chitosan-GL bound to the islet surface gradually increased. As measured by glucose-stimulated insulin secretion (GSIS), CCK-8 assay, and SA-β-gal staining, Glycol chitosan-GL @islets were more viable, produced more insulin, and scavenged ROS molecules than unmodified islets. Also, in a co-culture with LPS-activated macrophages (RAW 264.7 cells), glycol chitosan-GL @islets reduced the immunological response and neutralized HMGB1 protein using CCK-8 assay, TNF-α ELISA. When the HMGB1 labeled Alexa594 (red) and glycol chitosan-GL labeled Alexa488 (green) overlap, a yellow signal is produced, indicating that HMGB1 has been neutralizing by glycol chitosan-GL. Notably, Glycol chitosan-GL @islets recovered normoglycemia and kept blood sugar levels 2-fold longer than unmodified islets when implanted into xenogeneic mice under the renal subcapsular membrane. Moreover, Tacrolimus, an immunosuppressive agent, and the Glycol Chitosan-GL @islets showed a synergistic impact that resulted in the sustained maintenance of blood glucose levels.

In summary, this study provides a new strategy for enhancing the effectiveness of islet transplantation for the treatment of diabetes by neutralizing HMGB1 activity for a cell-based transplantation therapy.