Cross-linked lipoic acid nanoparticles (cLA) exhibit significant potential in oral nano-delivery due to their high stability and unique barrier penetration ability, which is mediated by the poly(disulfide) backbone. However, the strong negative charge on their surface (approximately -68 mV) generates strong electrostatic repulsion with the mucus layer and intestinal epithelial cells, limiting the trans-barrier transport efficiency of the nanoparticles. To address this issue, we constructed a cross-linked lipoic acid nanoparticle platform (cLAS) modified with zwitterionic sulfobetaine. This modification strategy effectively reduces the surface potential to approximately -11 mV, significantly weakening the electrostatic repulsion and ensuring that the inherent penetration advantage of the poly(disulfide) backbone is fully utilized. Simultaneously, the hydration layer formed on the surface can effectively shield the interaction between cLAS and the hydrophobic domains of mucins. Pharmacokinetic experiments conducted in Sprague-Dawley rats confirmed that the relative bioavailability of coumarin-6 encapsulated in cLAS increased to 1.49-fold compared to the cLA-loaded group. These results indicate that sulfobetaine-modified cLAS represents a highly efficient oral drug delivery platform with clinical translation potential.
Hou et al. (Thu,) studied this question.