Development and assessment of mucus-penetrating nanoparticles for mucosal delivery of mRNA vaccines
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Date
2025-07-01
Authors
Kayode, Ebunoluwa Olabisi
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Abstract
Mucosal vaccines are a brilliant strategy to trigger both cellular and humoral immune responses, providing robust protection and preventing infections at their point of entry. While mRNA vaccines have emerged as safe and effective forms of vaccines for immunization, delivering them to the respiratory mucosa remains a challenge due to their fragile nature and physiological barriers. To address this, we developed a hybrid lipid–polymer nanoparticle system, termed LipoParticles (LPs), incorporating a novel muco-penetrating lipid called D03-3. We systematically varied the ratio of cationic lipid to D03-3 to optimize LPs with stable physical properties and strong gene delivery performance in vitro.
Three lead formulations were selected and evaluated in RPMI2650 and DC2.4 cell lines using flow cytometry, comparing their protein expression levels and cellular uptake to conventional lipid nanoparticles (LNPs) and LPs without D03-3 (mucLP), both before and after nebulisation. Our findings show that LPs are more resistant to the shear stress of nebulisation than LNPs, and they deliver mRNA more efficiently to dendritic cells. Notably, formulations with higher levels of D03-3 enhanced transfection efficiency in DC2.4 cells. In vivo experiments following nasal instillation in mice provided preliminary basis that D03-3 may improve mucosal penetration of LPs across the nasal epithelium.
This study not only highlights the role of D03-3 in enhancing mRNA delivery and protein expression in immune cells but also introduces a promising new nanovector designed specifically for mRNA vaccine delivery to the upper or lower respiratory tract, either by nasal administration or nebulisation, respectively.
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Keywords
mRNA vaccine, Mucosal delivery, Nebulisation, Hybrid nanovectors