Progress and challenge of hepatitis B virus mucosal vaccines.

Hepatitis B virus (HBV) is highly contagious, primarily infected through mucous membranes or broken skin exposed to infected body fluids. Conventional injectable vaccines, which require cold chain storage and trained personnel, elicit systemic immunity but fail to establish effective immune protection at mucosal sites where HBV enters. Mucosal vaccines administered orally or intranasally can induce both mucosal and systemic immune responses, offering enhanced protection along with advantages such as ease of administration, no need for cold chain, and reduced reliance on healthcare workers. Given the critical potential of mucosal vaccines in addressing HBV transmission, this review systematically summarizes recent progress in mucosal HBV vaccine development. It covers the evolution of vaccine platforms, from early nasal sprays to advanced oral delivery systems utilizing plant-based antigens, synthetic nanomaterials, and exosomes derived from sources like milk. The advantages and challenges of these platforms are systematically analyzed, with particular attention given to exosome-based systems, which demonstrate excellent biocompatibility and strong potential for effective mucosal delivery. Furthermore, this review discusses future trends in the field, including engineering strategies for targeted delivery and scalable production. Ultimately, this review aims to bridge research and application by offering clear insights and directions to advance the development of practical mucosal HBV vaccines.