Intranasal Vaccine Adjuvants and Delivery Platforms: From Barrier Mechanisms to Clinical Translation

As a non-invasive mucosal immunization strategy, intranasal vaccines are highly promising for preventing respiratory infectious diseases. Among them, recombinant subunit vaccines represent a safe and ideal option, as they induce targeted mucosal immunity without the safety risks associated with live-vectored or nucleic acid vaccines. However, nasal mucosal defenses rapidly clear antigens before immune activation, limiting protective efficacy. Therefore, intranasal vaccine adjuvants-key regulators of immune response intensity, duration, and type-are essential to overcome mucosal tolerance and improve immunogenicity. Based on a systematic search and analysis of 127 peer-reviewed articles (2010-2026) in PubMed, Web of Science, and Embase, this study comprehensively summarizes the mechanisms, applications, and limitations of existing and candidate adjuvants for intranasal vaccines. This review systematically categorizes and discusses the nasal mucosal barrier, major adjuvant types (e.g., pattern recognition receptor agonists, cytokine adjuvants, and carrier adjuvants), and their mechanisms of action. It also identifies key bottlenecks: insufficient mucosal targeting, inconsistent global safety evaluation standards for adjuvants, and interference from pre-existing antibodies in humans. Furthermore, this review highlights future development directions, including biomimetic adjuvants, pH-responsive nanoadjuvants, and thermostable vaccine formulations. This systematic review clarifies key scientific and technical barriers in intranasal vaccine adjuvant development. The findings provide valuable references for advancing the translation of intranasal vaccines from emergency countermeasures to routine, accessible preventive tools for respiratory infectious diseases.