Enantioselective Oral Absorption of Molecular Chiral Mesoporous Silica Nanoparticles

Abstract Inspired by the unique pharmacological effects of chiral drugs in the asymmetrical body environments, it is assumed that the chirality of nanocarriers is also a key factor to determine their oral adsorption efficiency, apart from their size, shape, etc. Herein, l / d ‐tartaric acid modified mesoporous silica nanoparticles ( l / d‐ CMSNs) are fabricated via a one‐pot cocondensation method, and focused on whether the oral adsorption of nanocarriers will be benefited from their chirality. It is found that l ‐CMSN performed better in the sequential oral absorption processes, including mucus permeation, mucosa bio‐adhesion, cellular uptake, intestinal transport and gastrointestinal tract (GIT) retention, than those of the d‐ chiral ( d‐ CMSN), racemic ( dl‐ CMSN), and achiral (MSN) counterparts. The multiple chiral recognition mechanisms are experimentally and theoretically demonstrated following simple differential adsorption on biointerfaces, wherein electrostatic interaction is the dominant energy. During the oral delivery task, l‐ CMSN, which is proven to be stable, nonirritative, biocompatible, and biodegradable, is efficiently absorbed into the blood (1.72–2.05‐fold higher than other nanocarriers), and helps the loaded doxorubicin (DOX) to achieve better intestinal transport (2.32–27.03‐times higher than other samples), satisfactory bioavailability (449.73%) and stronger antitumor effect (up to 95.43%). These findings validated the dominant role of chirality in determining the biological fate of nanocarriers.