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Engineered Low-Endotoxin Bacterial Biomimetic Vesicles for Enhanced Oral Dual-Antigen Subunit Vaccine Delivery

文献类型： 外文期刊

作者： Xuegang Shen;Shujie Wang;Kunying Qiu;Zeqing Liu;Xiaoxiao Tian;Fandan Meng;Yan-Dong Tang;Haiwei Wang;Mingxia Sun;Xue-Hui Cai;Tong-Qing An;Yong-Bo Yang

关键词： bacterial biomimetic vesicle; combination subunit vaccine; low‐endotoxin engineering; mucosal immunity; oral antigen delivery.

期刊名称： Journal of Extracellular Vesicles

ISSN：

年卷期： 2025 年

页码：

收录情况： SCIE（2025版）

摘要： Subunit vaccines are promising for disease prevention because of their safety and cost-effectiveness. However, their efficacy is limited by low immunogenicity and gastrointestinal degradation after oral administration. To address this issue, low-endotoxin Salmonella choleraesuis strain SC-L3 was engineered via lipid A modification to generate bacterial biomimetic vesicles (BBVs) with reduced endotoxin activity. BBVs were functionalized using ClyA-embedded SpyCatcher and Streptococcus protein G for dual antigen coupling, and further coated with chitosan oligosaccharides (COS) to enhance mucosal penetration and gastrointestinal stability. Using mCherry as a model antigen, we obtained optimized mCherry-CSS-BBV@COS that showed high antigen protection rates (83% and 63% in simulated gastric and intestinal fluids, respectively), capacity for lysosomal escape and effective stimulation of M1 macrophage polarization in vitro. Oral administration of mCherry-CSS-BBV@COS elicited robust systemic IgG and mucosal sIgA responses in mice. Furthermore, dual-antigen BBV conjugates (GDH-gD-Fc-CSS-BBV@COS) co-delivering Streptococcus suis glutamate dehydrogenase and pseudorabies virus gD-Fc induced antigen-specific humoral, mucosal and cellular immunity, conferring complete protection against lethal challenges with the respective pathogens. In summary, we generated a versatile, low-endotoxin BBV platform for oral combination subunit vaccines, offering a novel strategy for protection against viral and bacterial infections.

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