Menthol–Fatty Acid HDES Boosts In Vitro Oral Bioavailability of Oleanolic Acid via Synergistic Digestive Release and Cellular Absorption

TL;DR

This study shows that a new solvent system improves the absorption of oleanolic acid in the gut, making it more effective for oral delivery.

Contribution

A novel menthol–fatty acid HDES system is introduced to enhance the bioavailability of oleanolic acid.

Findings

The HDES system increased OA's in vitro bioavailability index by 9.3-fold compared to ethanol.

OA bioaccessibility reached 14.30% with HDES versus 4.90% with ethanol during digestion.

Cellular uptake of OA improved to 25.79% with HDES compared to 4.71% with ethanol.

Abstract

To improve the oral bioavailability of oleanolic acid (OA), this study developed a menthol–fatty acid-based hydrophobic deep eutectic solvent (HDES) system. Through a comprehensive evaluation using in vitro simulated digestion and Caco-2 cell transport models, the short-chain HDES was found to increase the apparent in vitro bioavailability index of OA by 9.3-fold compared to conventional ethanol systems, with efficacy showing clear fatty acid chain-length dependence. The mechanism was systematically investigated through spectral characterization and cellular studies, revealing a two-stage enhancement process: during the digestion phase, HDES significantly improved OA bioaccessibility to 14.30% compared to 4.90% with ethanol; during the absorption phase, it markedly increased cellular uptake to 25.79% versus 4.71% with ethanol. Molecular analysis indicated that the optimal hydrophobicity and diffusion properties of HDES contributed to this enhancement. This study reveals a fatty acid chain-length-dependent mechanism in HDES-facilitated OA delivery, providing a tunable strategy for enhancing the absorption of hydrophobic bioactive compounds.

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