Semaglutide (SMG) is a glucagon-like peptide-1 receptor agonist with a promising efficacy and safety profile that is widely used for reducing obesity by targeting the appetite control centres in the brain and for type 2 diabetes management by enhancing insulin release and suppressing glucagon secretion. SMG is currently administered subcutaneously that is invasive with reduced patient compliance or orally leading to decreased efficacy owing to first-pass effects. In this study, a nanoparticle (NP) formulation of SMG was developed using a thermoresponsive and biocompatible synthetic polymer, PNPHO (poly(N-isopropylacrylamide-co-(N-acryloxysuccinimide)-co-(polylactide/-hydroxy methacrylate)-co-(oligo (ethylene glycol)), to investigate its potential to enhance nasal mucosal absorption and prolong residence time via the needle-free intranasal (IN) route. The NP formulation was characterized in vitro for physicochemical parameters, stability, mucoadhesion, regional nasal deposition, drug release profile, and cellular permeation, and in vivo for glucose sensitivity and biodistribution. Monodispersed NPs displayed an average size of 26.14 ± 0.19 nm, a negative surface charge with high SMG encapsulation (89%), improved stability against enzymatic degradation and increased permeation across nasal epithelial cells in vitro compared to SMG alone (p < 0.0001). In contrast, it reduced transport across hCMEC/D3 BBB cells. Nasal cast studies revealed greater NP deposition in the turbinates compared to the free drug. In vivo, the NP formulation demonstrated prolonged nasal retention of the formulation within the sinus region along with an improved glucose tolerance with a 24 h dosing regimen, showing an extended period of pharmacological activity that can be utilized for reducing dosing frequency. No detectable brain fluorescence was observed in vivo. Overall, these findings corroborate the potential of IN delivery of thermoresponsive SMG-PNPHO NP formulation with increased efficacy compared to current SMG delivery modes.
