Cell-penetrating peptides as a potential drug delivery system for effective treatment of diabetes

Background/Purpose: Type 2 diabetes (T2D) is characterized by hyperglycemia resulting from the body’s inability to produce and/or use insulin. Patients with T2D often have hyperinsulinemia, dyslipidemia, in-flammation, and oxidative stress, which then lead to hypertension, chronic kidney disease, cardiovascular dis-ease, and increased risk of morbidity and mortality (9^th leading cause globally). Insulin and related pharmacological therapies are widely used to manage T2D, despite their limitations. Efficient drug delivery systems (DDS) that control drug kinetics may decrease side effects, allow for efficient targeting, and increase the bioavailabili-ty of drugs to achieve maximum therapeutic benefits. Thus, the development of effective DDS is crucial to beat diabetes. Methods: Here, we introduced a highly bioavailable vector, cell-penetrating peptides (CPPs), as a powerful DDS to overcome limitations of free drug administration. Results: CPPs are short peptides that serve as a potent tool for delivering therapeutic agents across cell mem-branes. Various cargoes, including proteins, DNA, RNA, liposomes, therapeutic molecules, and nanomaterials, generally retain their bioactivity upon entering cells. The mechanisms of CPPs/cargoes intracellular entry are classified into two parts: endocytic pathways and direct membrane translocation. In this article, we focus on the applications of CPPs/therapeutic agents in the treatment of diabetes. Hypoglycemic drugs with CPPs intervention can enhance therapeutic effectiveness, and CPP-mediated drug delivery can facilitate the actions of insulin. Numerous studies indicate that CPPs can effectively deliver insulin, produce synergistic effects with immuno-suppressants for successful pancreatic islet xenotransplantation, prolong pharmacokinetics, and retard diabetic nephropathy. Conclusion: We suggest that CPPs can be a new generation of drug delivery systems for effective treatment and management of diabetes and diabetes-associated complications.