Obesity is a chronic, relapsing metabolic disorder associated with insulin resistance, dyslipidemia, and related complications. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide (SEMA), exhibit robust therapeutic efficacy, their clinical application is limited by low oral bioavailability. Here, we report a dual-transporter-targeted oral nanomicellar platform (SGT-M) designed to overcome these limitations. SEMA was electrostatically complexed with glucosamine and taurolithocholate to enable transporter-mediated recognition, followed by incorporation into an n-dodecyl-β-D-maltoside-based nanomicelle. The optimized SGT-M had a particle size of 64.7 ± 1.27 nm and near-complete drug incorporation. In vitro, SGT-M enhanced apparent permeability by 28.8-fold in Caco-2/HT-29-MTX-E12 monolayers, while in situ intestinal perfusion demonstrated a 12.6-fold increase in effective permeability. Oral administration achieved a relative bioavailability of 4.62%. Mechanistic studies revealed a multivalent absorption pathway involving dual targeting of the apical sodium-dependent bile acid transporter (ASBT) and glucose transporter 2 (GLUT2), together with clathrin- and caveolae/lipid-mediated endocytosis. In a high-fat-diet-induced obese mouse model, daily oral administration of SGT-M produced dose-dependent therapeutic effects; at 5 mg/kg, it reduced body weight by 30.3% and fasting glucose by 65.6%, while improving HbA1c and HOMA-IR and decreasing adipose tissue mass. Notably, the highest oral dose of SGT-M produced therapeutically meaningful outcomes that approached those observed with subcutaneous SEMA (0.5 mg/kg) under the experimental conditions used. Collectively, SGT-M represents an engineered oral SEMA delivery system that enables effective systemic exposure and therapeutic efficacy, offering a promising strategy to transform injectable peptide therapies into clinically viable oral formulations.
