Engineered Nanoparticles inside a Microparticle Oral System for Enhanced Mucosal and Systemic Immunity.

Area of Science:

• Immunology
• Biotechnology
• Vaccine Development

Background:

• Oral antigen delivery faces challenges from gastrointestinal barriers like enzymes, mucus, and tight junctions.
• Transcytosis through follicle-associated epithelium (FAE) is critical for oral vaccine efficacy, with M-cells traditionally targeted.
• M-cell targeting has limitations due to their low population (<1%) and has contributed to oral vaccine failures in clinical trials.

Purpose of the Study:

• To challenge the M-cell-centric approach in oral vaccination by developing a novel antigen delivery system.
• To design a tandem peptide-based system capable of targeting both M-cells and enterocytes within the FAE.
• To evaluate the system's ability to overcome barriers and elicit both mucosal and systemic immune responses.

Main Methods:

• A novel tandem peptide (FAE-targeting + cell-penetrating) was designed and attached to a smart delivery system.
• The system was engineered to overcome enzymatic and mucosal barriers in the gastrointestinal tract.
• In vitro and in vivo studies assessed dendritic cell maturation, T-lymphocyte production (CD4+, CD8+), and immune (IgA, IgG) responses.

Main Results:

• The engineered system successfully targeted FAE (enterocytes and M-cells) and penetrated enterocytes to reach subepithelial dendritic cells.
• In vitro, significant dendritic cell maturation and activation were observed, indicated by increased CD40, CD86, MHC I, and cytokine (TNF-α, IL-6, IL-10) levels.
• In vivo, high production of CD4+ and CD8+ T-lymphocytes, along with significant mucosal (IgA) and systemic (IgG) immunity, was confirmed.

Conclusions:

• This study presents the first tandem peptide targeting both M-cells and enterocytes for enhanced FAE delivery.
• The novel system effectively overcomes oral delivery barriers and elicits potent mucosal and systemic immunity.
• This approach offers a promising strategy to improve oral vaccine efficacy beyond traditional M-cell targeting.