Oral Delivery of Semaglutide via Nanostructured Lipid Carriers (NLCs): A Review of Formulation, Stability, and Intestinal Uptake

Abstract

Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated significant efficacy in obesity management. However, its therapeutic potential is limited by poor oral bioavailability and enzymatic degradation in the gastrointestinal tract, necessitating subcutaneous administration. Nanostructured lipid carriers (NLCs) offer a promising alternative by encapsulating semaglutide within a lipid matrix that enhances stability, protects against proteolysis, and facilitates intestinal absorption. This review explores the formulation strategies, pharmacokinetic improvements, and therapeutic relevance of semaglutide-loaded NLCs. NLCs are composed of solid and liquid lipids stabilized by surfactants such as Tween 80 and Poloxamer 188, which together create a disordered matrix capable of accommodating hydrophilic peptides. Optimization of lipid selection, surfactant concentration, and homogenization parameters is critical to achieving high encapsulation efficiency and sustained release. Pharmacokinetic studies reveal that NLCs significantly improve systemic exposure and half-life of semaglutide, while pharmacodynamic evaluations show enhanced appetite suppression and weight reduction in preclinical models. Despite these advances, challenges remain in formulation stability, mucosal permeability, and large-scale manufacturing. Strategies such as mucoadhesive coatings, PEGylation, and chitosan modification are being explored to improve intestinal uptake. Regulatory harmonization and long-term safety evaluations are essential for clinical translation. Semaglutide-loaded NLCs represent a transformative platform for non-invasive obesity therapy, with the potential to improve patient adherence and therapeutic outcomes. Continued research and innovation in lipid-based nanocarriers may redefine the future of peptide drug delivery.