Stimuli-Responsive Nasal in situ Gel Drug Delivery Systems: from Material Design to Clinical Translation

As a novel drug delivery system responsive to environmental stimuli (temperature, pH, ionic strength, etc). nasal in situ gels undergo phase transition to provide breakthrough solutions for precision and long-term management of nasal disorders through the integration of targeted therapy and sustained-release technology. Following nasal administration, the liquid formulation rapidly transforms into a semi-solid gel depot on the mucosal surface, significantly prolonging drug residence time and reducing drug loss due to mucociliary clearance. This process enhances local drug concentration and therapeutic persistence. Incorporating mucoadhesive technology and controlled-release drug-loading systems, this platform enables precise delivery of anti-inflammatory, antihistaminic, and immunomodulatory agents to lesion sites. It effectively mitigates systemic side effects (e.g. drowsiness, hepatic/renal burden) associated with conventional dosage forms while reinforcing nasal mucosal barrier repair. Clinical studies confirm its superior efficacy and safety profile in conditions requiring long-term therapy, including allergic rhinitis, sinusitis, and central nervous system disorders. Its mild gelation properties enhance patient tolerance, and single/every-other-day dosing regimens significantly improve compliance. Further optimization of release kinetics through multi-level drug-loading techniques (e.g. composite nanoparticles) demonstrates potential in gene therapy and vaccine delivery. This review systematically examines material design strategies, drug release mechanisms, clinical advancements, and translational challenges, with focused analysis on the impact of gelation kinetics on delivery efficiency, bottlenecks in scaled-up production. The work aims to provide theoretical foundations for optimized design and clinical translation while exploring future prospects for multifaceted applications in the era of precision medicine.