Respiratory mucosal immunity: Biological functions, diseases, prevention and therapy

Respiratory mucosal (RM) immunity is a highly specialized and dynamic network that safeguards the airways from inhaled pathogens while preserving tissue homeostasis. Acting as the body's first line of defense, RM immunity integrates immune tolerance, barrier protection, immune surveillance, tissue repair, and the establishment of long-term immunological memory. Dysregulation of these processes contributes to a broad spectrum of diseases, including acute viral and bacterial infections, fungal colonization, and chronic inflammatory disorders, highlighting the urgent need for effective preventive strategies targeting the respiratory mucosa. The unprecedented global impact of coronavirus disease 2019 (COVID-19) has further highlighted this need and catalyzed rapid advances in vaccines capable of inducing both local and systemic immunity at the respiratory portal of entry, alongside progress in inhalable antibody therapies. This review first summarizes the principal biological functions of the respiratory mucosa and the underlying mechanisms, followed by an overview of immune dysregulation associated with respiratory diseases. It then highlights recent advances in mucosal intervention strategies, with a particular focus on the development of RM vaccine platforms-including live-attenuated, inactivated, viral vector, protein subunit, and mRNA vaccines. It further discusses next-generation RM vaccine strategies emphasizing upper airway immunity, broadened antigen design and intranasal safety. Together, these advances provide a conceptual and translational framework for advancing RM-based interventions against respiratory pathogens.