A konjac glucomannan-based hydrogel delivery system induces trained immunity via enhanced oxidative phosphorylation...

Subunit vaccines represent a leading platform in modern vaccinology due to their defined antigenicity and favorable safety profiles. However, their efficacy requires advanced adjuvants to overcome limited immunogenicity. While plant-derived polysaccharides are widely recognized for their immunostimulatory properties, their capacity to induce trained immunity remains largely unexplored. This study demonstrates, for the first time, that a Konjac glucomannan (KGM)-based hydrogel can induce trained immunity. Specifically, we developed an injectable hydrogel composed of KGM and carboxymethyl cellulose (CMC) that confers protection against Staphylococcus aureus infection via trained immunity. Mechanistically, peritoneal macrophages from KGM/CMC-trained mice exhibited a metabolic shift toward oxidative phosphorylation, accompanied by the significant accumulation of key metabolites such as succinate and palmitate. This KGM/CMC-induced trained immunity provided rapid protection within 3 days and broad-spectrum defense against Gram-positive bacteria. Furthermore, the hydrogel synergized with specific antigens and aluminum adjuvants to significantly potentiate single-dose subunit vaccines, increasing the survival rate of challenged mice to 50%. These findings identify the KGM/CMC as a promising delivery vehicle for vaccines leveraging trained immunity and establish a proof-of-concept for adapting plant-derived bioactive polysaccharides into next-generation immunomodulatory tools.