Computationally guided deep eutectic solvent with dual solubilizing and self-emulsifying functions for delivery of hydrophobic bioactives

Deep eutectic solvents (DES) show potential in increasing the solubility of hydrophobic bioactives, but the vast variety and the dilution‑induced destabilization of the hydrogen bond network (HBN) limit their practical applicability. In this work, we employed conductor-like screening model for real solvents (COSMO-RS) calculations to rapidly screen DES with high solubility and capacity to form a self-emulsifying delivery system (SEDS). Among different types of DES, choline chloride-polyethylene glycol (ChCl-PEG) exhibited outstanding solubility capacities for hydrophobic bioactives such as resveratrol, quercetin, and curcumin, and also possessed excellent properties for stabilizing the oil-water interface. The experimental results were consistent with the calculations. Notably, the curcumin solubility is among the highest to date, reaching 110.04 mg/mL, 14-fold higher than the classical ChCl‑glycerol DES. Mechanistic investigations further demonstrated that the regulated HBN dominated the monomeric dispersion of bioactives, effectively inhibiting molecular aggregation and enhancing dissolution. Upon simple dilution, DES spontaneously formed uniform nanoemulsions (100 nm, PDI 0.22) with fish oil and Tween 80. The as-prepared SEDS showed enhanced bioaccessibility and biocompatibility in coupled simulated digestion and Caco-2 studies, demonstrating a cellular uptake rate of 16.97%, which is 1.43 × higher than that of the classic propylene glycol-based SEDS and 9.75 × higher than that of free curcumin. This work realizes rapid theoretical screening of high-performance DES and mitigates dilution-induced destabilization via droplet-mediated water isolation. The strategy of using DES as a co-surfactant provides a promising and scalable approach for hydrophobic bioactive delivery.