Deep Eutectic Solvent-Assisted Synergistic Technologies for the Extraction of Natural Bioactive Compounds: Enhancement Mechanisms, Application Advances, and Challenges

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Abstract
Deep eutectic solvents (DESs) have emerged as promising green extraction media for natural bioactive compounds, offering tunable physicochemical properties, biocompatibility, and lower toxicity than conventional organic solvents. However, the high viscosity of DESs limits mass transfer efficiency, necessitating integration with auxiliary technologies to overcome this intrinsic constraint. Unlike previous reviews that focus on DESs coupled with a single auxiliary technique, this review for the first time integrates DESs with ultrasound, microwave, enzymatic assistance, and multi-technique hybrid systems into a unified framework, critically comparing their enhancement mechanisms, applicability boundaries, and industrial feasibility. This review systematically examines the non-covalent interactions between DES components and target compounds, including hydrogen bonding, van der Waals forces, and electrostatic interactions, and discusses how these interactions guide the rational selection of hydrogen bond acceptors (HBAs) and donors (HBDs) for specific compound classes. We analyze the distinct mechanisms by which ultrasound, microwave, and enzymatic assistance synergistically enhance DES extraction performance, with particular attention to viscosity reduction, cell wall disruption, and biocatalytic compatibility. Recent advances in the extraction of polyphenols, alkaloids, terpenoids, and polysaccharides are summarized to illustrate the practical application of these principles. Finally, we discuss current challenges in industrial scale-up, including solvent recovery, equipment adaptation for high-viscosity media, and regulatory considerations, and outline future directions toward intelligent solvent design and continuous processing. By integrating molecular-level mechanistic insights with process engineering perspectives, this review provides a comprehensive framework for the optimization and application of DES-based extraction technologies.

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