Semaglutide is an effective anti-obesity peptide, but repeated subcutaneous injections may reduce its acceptability for long-term therapy. We prepared semaglutide-loaded poly(vinyl alcohol) (PVA) dissolving microneedles (Sema-MNs) by sequential vacuum-assisted molding and room-temperature drying. The 15 × 15 arrays concentrated Cy5-labelled semaglutide toward the needle tips, resisted axial compression, penetrated rat skin, and partially dissolved within 5 min; skin barrier function approached baseline within 4-6 h. Sema-MNs contained 29 ± 2 μg semaglutide per patch, with an apparent delivered amount of 18 ± 2 μg (63 ± 3%; n = 3), and released more than 90% of the Sema-Cy5-associated cargo within 30 min. In high-fat-diet-induced obese rats, once-daily Sema-MN treatment for 7 days reduced food intake and body weight. Treatment also decreased adipocyte size and hepatic lipid accumulation, improved glucose tolerance and serum metabolic indices, and reduced hypothalamic neuropeptide Y immunofluorescence relative to the disease and unloaded-microneedle controls. No evident renal biochemical or major-organ histopathological abnormalities were observed during the study. These findings support the feasibility of a compositionally simple, rapid-release PVA microneedle system for transdermal semaglutide administration.
