Mechanistic Insights into GLP-1 and DPP-4 Pathways: Opportunities for Nano-Delivery and β-Cell Protection and Regeneration
Muhammad Raza, Jun-Sub Kim, Hyang-Yeol LeeIntroduction/Objective:
Diabetes mellitus is characterized by persistent hyperglycemia and progressive β-cell dysfunction. GLP-1 receptor agonists improve glycemic control and weight management, with cardiovascular and renal benefits reported in some patients, while DPP-4 inhibitors generally have more modest effects. Limitations such as peptide instability, administration challenges, tolerability, cost, and long-term treatment burden have encouraged the development of advanced drug-delivery and regenerative strategies.
Methods:
This narrative review evaluates the molecular mechanisms of GLP-1 and DPP-4 signaling and the therapeutic potential of emerging approaches for diabetes management. The literature was reviewed with particular emphasis on nanotechnology-based drug-delivery systems, geneand mRNA-based therapies, and cell-based strategies for incretin therapy, β-cell preservation, and regeneration. Evidence regarding therapeutic efficacy, delivery-system characteristics, development status, advantages and limitations, and barriers to clinical translation was critically examined to provide an integrated overview of current advances and future opportunities.
Results:
GLP-1 signaling and DPP-4 inhibition improve glucose-dependent insulin secretion while supporting β-cell survival and function. Nanotechnology-based delivery systems show potential to improve peptide stability, bioavailability, controlled release, and tissue targeting, although most approaches remain at the preclinical stage. Gene, mRNA, and cell-based approaches have shown β-cell regeneration or preservation in animal models; however, clinically meaningful endogenous β-cell regeneration has not yet been established in humans. Key barriers to clinical translation include long-term biosafety, immunogenicity, manufacturing scalability and reproducibility, regulatory requirements, cost, and clinical implementation.
Discussion:
Combining cutting-edge delivery technologies with well-established incretin pharmacology may help overcome some of the drawbacks of conventional treatments. However, nano-delivery, gene, mRNA, and regeneration techniques are still in preclinical or early research stages; they should be clearly distinguished from clinically proven treatments. To determine their longterm efficacy, safety, and clinical value, more validation in well-organized clinical trials is needed.
Conclusion:
GLP-1 receptor agonists and DPP-4 inhibitors remain established components of incretin- based therapy, while advanced nanotechnology-based delivery systems offer promising opportunities but are largely supported by preclinical evidence. Future research should highlight the combination of precision medicine, pharmacogenomics, artificial intelligence-assisted treatment, and optimized drug-delivery systems to improve therapeutic efficacy and patient-specific outcomes. Smart glucose-responsive nanocarriers may further allow controlled, targeted, and adaptive drug release, supporting the development of more precise incretin-based therapies.