Innovative mucosal nanocarrier systems for enhanced immune response against respiratory pathogens

INTRODUCTION: Effective pulmonary vaccination remains limited by the pulmonary surfactant (PS) barrier and inefficient intracellular delivery of vaccine cargo to alveolar antigen-presenting cells, particularly alveolar macrophages. Inspired by the natural compatibility of alveolar macrophage-derived vesicles with the alveolar environment, we developed biomimetic alveolar macrophage membrane vesicles (AMVs) as a mucosal nanocarrier platform. OBJECTIVES: This study aimed to develop a nanovaccine platform that addresses key extracellular and intracellular barriers in the lung and to evaluate its immunogenicity and protective efficacy in multiple respiratory pathogen models. METHODS: AMVs were engineered to improve performance in the PS environment and to achieve preferential uptake by alveolar macrophages. An Antigen Capture and Cytosolic Delivery System (ACCDS) was incorporated, comprising: (1) an engineered surfactant protein A domain for broad pathogen binding; (2) a pH-responsive listeriolysin O module designed to facilitate endo/lysosomal escape and enhance cytosolic access of cargo; and (3) encapsulated Poly(I:C) to activate TLR3 and support RIG-I/MDA5-associated signaling. RESULTS: T cells and was accompanied by IL-18-associated metabolic remodeling. In prime-boost studies, it conferred complete protection in lethal influenza and pseudorabies virus challenge models and reduced pulmonary burden in a Mycoplasma infection model. CONCLUSION: AMV-ACCDS-Poly(I:C) provides a biomimetic strategy to address key barriers in pulmonary vaccination and supports the potential of membrane-based mucosal vaccine systems for protection against respiratory pathogens.