Enhancing Mucus Penetration and Intestinal Epithelial Transport of Diacylglycerol Nanoparticles by Surface-Modification

Oral delivery of bioactive peptides by nanoparticles (NPs) plays an important role in drug administration for treating diseases. However, the delivery efficiency normally faces challenges such as gastrointestinal tract environment and barriers. Selecting the appropriate lipids and modulating the surface characteristics by polymers are critical to overcome the deficiencies. Herein, diacylglycerol (DAG) solid lipid nanoparticles (DAG-SLNs) modified with various surface agents were fabricated with glyceryl tristearate (TG) and cetyl palmitate (CP) as lipid controls. The results indicated that polydopamine (PDA) and polyethylene glycol (PEG) modifications reduced the hydrophobic interactions between nanoparticles and mucin, which subsequently enhanced penetration. Meanwhile, the low surface hydrophobicity of DAG particles resulted in higher mucus penetration ability than TG and CP SLNs. Caco-2/HT-29 uptake of particles primarily occurred via the lipid raft/caveolae-mediated pathway. The interaction between the quinone structure of PDA and the hydroxyl groups endowed the DAG particles with excellent transmembrane capability. The particles showed high delivery efficiency for flaxseed cyclopeptide with increased anti-inflammatory efficiency due to the high permeability in Caco-2/HT-29 and RAW 264.7 macrophages. This study provides insights into modulating the interaction of particles with cells in the mucosa and provides essential support for the rational design and application of lipid nanocarriers with high delivery efficiencies.