A Thermosensitive Mucoadhesive Hydrogel for Nasal Influenza Vaccine Delivery Elicits Robust Systemic and Mucosal Immunity

Influenza virus invades the host through the respiratory mucosa, making local immunity at the infection site critical for blocking transmission. However, the nasal mucus-cilia clearance barrier severely hinders antigen retention and limits the efficacy of mucosal vaccines. Here, we developed a thermosensitive hydrogel based on cationic chitosan (CS) for codelivery of hemagglutinin (HA) protein and CpG adjuvant (Gel-Pro-CpG). This platform remains a low viscosity liquid at 25°C for convenient nasal administration, and rapidly undergoes sol-gel transition upon contact with the nasal mucosa (∼34°C), forming a mucoadhesive porous depot that significantly prolongs antigen residence and resists ciliary clearance. In a mouse model, Gel-Pro-CpG synergistically elicited strong immune responses and elevated secretory IgA (sIgA) titers in both nasal mucosa and lungs, establishing an effective mucosal immune barrier. Immunization with Gel-Pro-CpG conferred complete protection against lethal H1N1 challenge, markedly reducing pulmonary viral loads and pathological damage. By overcoming nasal physiological barriers and enabling sustained antigen release, this thermosensitive mucoadhesive hydrogel platform offers a promising strategy for inducing coordinated mucosal-systemic immunity and provides a new direction for developing highly effective vaccines against respiratory infections.